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1
ARTICLE

Lipid Profiles of Cardiovascular & Inflammatory Diseases

Olya Vvedenskaya, Henri Deda

Lipidome profiles in the blood plasma of patients with cardiovascular diseases (CVD) and ischemic stroke (IS), as well as systemic lupus erythematosus (SLE) were analyzed. For this purpose, they analyzed the blood plasma of 427 individuals, including the control group, with shotgun lipidomics technology. This allowed for the detection, identification, and quantification of 596 lipids. This study showed that mass spectrometry analysis of plasma lipids is a promising tool for differential diagnosis of various atherosclerosis-related vascular diseases, such as cardiovascular diseases and ischemic stroke.

Link: lipotype.com/cardiovascuar-inflammatory-disease

articles
clinical, cvd
2
nature neuroscience

TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury

Alessandro Zambusi, Klara T Novoselc, Saskia Hutten, Sofia Kalpazidou, Christina Koupourtidou, Rico Schieweck, Sven Aschenbroich, Lara Silva, Ayse S Yazgili, Frauke van Bebber, Bettina Schmid, Gabriel Möller, Clara Tritscher, Christian Stigloher, Claire Delbridge, Swetlana Sirko, Zeynep I Günes, Sabine Liebscher, Jürgen Schlegel, Hananeh Aliee, Fabian Theis, Silke Meiners, Michael Kiebler, Dorothee Dormann, Jovica Ninkovic

Decreasing the activation of pathology-activated microglia is crucial to prevent chronic inflammation and tissue scarring. In this study, we used a stab wound injury model in zebrafish and identified an injury-induced microglial state characterized by the accumulation of lipid droplets and TAR DNA-binding protein of 43 kDa (TDP-43)+ condensates. Granulin-mediated clearance of both lipid droplets and TDP-43+ condensates was necessary and sufficient to promote the return of microglia back to the basal state and achieve scarless regeneration. Moreover, in postmortem cortical brain tissues from patients with traumatic brain injury, the extent of microglial activation correlated with the accumulation of lipid droplets and TDP-43+ condensates. Together, our results reveal a mechanism required for restoring microglia to a nonactivated state after injury, which has potential for new therapeutic applications in humans. Link: doi.org/10.1038/s41593-022-01199-y

publications
organ/tissue, inflammation, zebrafish, neuro
3
PNAS

VpdC is a ubiquitin-activated phospholipase effector that regulates Legionella vacuole expansion during infection

Xiao Li, D Eric Anderson, Yuen-Yan Chang, Michal Jarnik, Matthias P Machner

Intravacuolar pathogens need to gradually expand their surrounding vacuole to accommodate the growing number of bacterial offspring during intracellular replication. Here we found that Legionella pneumophila controls vacuole expansion by fine-tuning the generation of lysophospholipids within the vacuolar membrane. Upon allosteric activation by binding to host ubiquitin, the type IVB (Dot/Icm) effector VpdC converts phospholipids into lysophospholipids which, at moderate concentrations, are known to promote membrane fusion but block it at elevated levels by generating excessive positive membrane curvature. Consequently, L. pneumophila overproducing VpdC were prevented from adequately expanding their surrounding membrane, trapping the replicating bacteria within spatially confined vacuoles and reducing their capability to proliferate intracellularly. Quantitative lipidomics confirmed a VpdC-dependent increase in several types of lysophospholipids during infection, and VpdC production in transiently transfected cells caused tubulation of organelle membranes as well as mitochondria fragmentation, processes that can be phenocopied by supplying cells with exogenous lysophospholipids. Together, these results demonstrate an important role for bacterial phospholipases in vacuolar expansion.

Link: doi.org/10.1073/pnas.2209149119

publications
human, cells, basic science
4
ARTICLE

Lipids and Kidney Disease in Diabetes

Olya Vvedenskaya, Henri Deda

A set of mice and cell culture experiments evaluated the disturbances in triglyceride synthesis as a key mechanism driving lipotoxicity in diabetic kidney disease. The diet in case of mice experiments, and enriched media in case of cell culture experiments, showed that oleic acid enhanced the production of triglycerides while palmitic acid increased the saturation levels of the diglyceride species and impaired triglyceride synthesis. Taken together, these results support the protective role of triglyceride-enriched lipid droplet formation and provide insights into the mechanisms leading to lipotoxicity in diabetes.

Link: lipotype.com/diabetic-kidney-disease

articles
organ/tissue, inflammation, mouse, diabetes
5
The Lipidomics Webinar

Role of Lipids in CNS Regeneration

Mikael Simons

Failure of regeneration capacity limits the restoration of nervous system functionality in demyelinating diseases such as multiple sclerosis. Yet, the responsible mechanisms are only partially understood. I will present data supporting a key role for lipid metabolisms (that is, lipid droplet biogenesis and cholesterol efflux) in phagocytes for regeneration of myelin. Stimulation of the lipid sensing Triggering receptor expressed on myeloid cells or nuclear liver X receptor are possible therapeutic strategies of how to enhance the capacity to regenerate lesioned tissue.

Link: lipotype.com/cns-regeneration

webinars
inflammation, mouse, aging, cells, diet, neuro, obesity, immuno
6
nature communications

TLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis

Kasparas Petkevicius, Henrik Palmgren, Matthew S Glover, Andrea Ahnmark, Anne-Christine Andréasson, Katja Madeyski-Bengtson, Hiroki Kawana, Erik L Allman, Delaney Kaper, Martin Uhrbom, Liselotte Andersson, Leif Aasehaug, Johan Forsström, Simonetta Wallin, Ingela Ahlstedt, Renata Leke, Daniel Karlsson, Hernán González-King, Lars Löfgren, Ralf Nilsson, Giovanni Pellegrini, Nozomu Kono, Junken Aoki, Sonja Hess, Grzegorz Sienski, Marc Pilon, Mohammad Bohlooly-Y, Marcello Maresca, Xiao-Rong Peng

The fatty acid composition of phosphatidylethanolamine (PE) determines cellular metabolism, oxidative stress, and inflammation. However, our understanding of how cells regulate PE composition is limited. Here, we identify a genetic locus on mouse chromosome 11, containing two poorly characterized genes Tlcd1 and Tlcd2, that strongly influences PE composition. We generated Tlcd1/2 double-knockout (DKO) mice and found that they have reduced levels of hepatic monounsaturated fatty acid (MUFA)-containing PE species. Mechanistically, TLCD1/2 proteins act cell intrinsically to promote the incorporation of MUFAs into PEs. Furthermore, TLCD1/2 interact with the mitochondria in an evolutionarily conserved manner and regulate mitochondrial PE composition. Lastly, we demonstrate the biological relevance of our findings in dietary models of metabolic disease, where Tlcd1/2 DKO mice display attenuated development of non-alcoholic steatohepatitis compared to controls. Overall, we identify TLCD1/2 proteins as key regulators of cellular PE composition, with our findings having broad implications in understanding and treating disease.

Link: doi.org/10.1038/s41467-022-33735-6

publications
human, organ/tissue, inflammation, mouse, cells
7
iScience

Ganglioside lipidomics of central nervous system myelination using direct infusion shotgun mass spectrometry

Martina Arends, Melanie Weber, Cyrus Papan, Markus Damm, Michal A Surma, Christopher Spiegel, Minou Djannatian, Shengrong Li, Lisa Connell, Ludger Johannes, Martina Schifferer, Christian Klose, Mikael Simons

Gangliosides are present and concentrated in axons, and implicated in axon-myelin interactions, but how ganglioside composition changes during myelin formation is not known. Here, we present a direct infusion (shotgun) lipidomics method to analyse gangliosides in small amounts of tissue reproducibly and with high sensitivity. We resolve the mouse ganglioside lipidome during development and adulthood and determine the ganglioside content of mice lacking the St3gal5 and B4galnt1 genes that synthesize most ganglioside species. Our results reveal substantial changes of the ganglioside lipidome during formation of myelinated nerve fibers. In sum, we provide insights into the central nervous system ganglioside lipidome with a quantitative and sensitive mass spectrometry method. Since this method is compatible with global lipidomic profiling, it will provide insight into ganglioside function in physiology and pathology.

Link: doi.org/10.1016/j.isci.2022.105323

publications
organ/tissue, mouse, aging, neuro, method
8
Nature communications

Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis

Sebastian Boland, Sharan Swarup, Yohannes A Ambaw, Pedro C Malia, Ruth C Richards, Alexander W Fischer, Shubham Singh, Geetika Aggarwal, Salvatore Spina, Alissa L Nana, Lea T Grinberg, William W Seeley, Michal A Surma, Christian Klose, Joao A Paulo, Andrew D Nguyen, J Wade Harper, Tobias C Walther, Robert V Farese Jr

Haploinsufficiency of GRN causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), which is cleaved to lysosomal granulin polypeptides. The function of lysosomal granulins and why their absence causes neurodegeneration are unclear. Here we discover that PGRN-deficient human cells and murine brains, as well as human frontal lobes from GRN-mutation FTD patients have increased levels of gangliosides, glycosphingolipids that contain sialic acid. In these cells and tissues, levels of lysosomal enzymes that catabolize gangliosides were normal, but levels of bis(monoacylglycero)phosphates (BMP), lipids required for ganglioside catabolism, were reduced with PGRN deficiency. Our findings indicate that granulins are required to maintain BMP levels to support ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. Lysosomal ganglioside accumulation may contribute to neuroinflammation and neurodegeneration susceptibility observed in FTD due to PGRN deficiency and other neurodegenerative diseases.

Link: doi.org/10.1038/s41467-022-33500-9

publications
human, organ/tissue, neuro
9
Journal of the American Heart Association

Lipidome‐ and Genome‐Wide Study to Understand Sex Differences in Circulatory Lipids

Rubina Tabassum, Sanni Ruotsalainen, Linda Ottensmann, Mathias J Gerl, Christian Klose, Taru Tukiainen, Matti Pirinen, Kai Simons, Elisabeth Widén, Samuli Ripatti

Despite well‐recognized differences in the atherosclerotic cardiovascular disease risk between men and women, sex differences in risk factors and sex‐specific mechanisms in the pathophysiology of atherosclerotic cardiovascular disease remain poorly understood. Lipid metabolism plays a central role in the development of atherosclerotic cardiovascular disease. Understanding sex differences in lipids and their genetic determinants could provide mechanistic insights into sex differences in atherosclerotic cardiovascular disease and aid in precise risk assessment. Herein, we examined sex differences in plasma lipidome and heterogeneity in genetic influences on lipidome in men and women through sex‐stratified genome‐wide association analyses.

We used data consisting of 179 lipid species measured by shotgun lipidomics in 7266 individuals from the Finnish GeneRISK cohort and sought for replication using independent data from 2045 participants. Significant sex differences in the levels of 141 lipid species were observed (P<7.0×10−4). Interestingly, 121 lipid species showed significant age‐sex interactions, with opposite age‐related changes in 39 lipid species. In general, most of the cholesteryl esters, ceramides, lysophospholipids, and glycerides were higher in 45‐ to 50‐year‐old men compared with women of same age, but the sex differences narrowed down or reversed with age. We did not observe any major differences in genetic effect in the sex‐stratified genome‐wide association analyses, which suggests that common genetic variants do not have a major role in sex differences in lipidome. Our study provides a comprehensive view of sex differences in circulatory lipids pointing to potential sex differences in lipid metabolism and highlights the need for sex‐ and age‐specific prevention strategies.

Link: doi.org/10.1161/JAHA.122.027103

publications
human, aging, plasma/serum, biomarker, cvd
10
ARTICLE

Lipid Metabolism & Microbiome of Dry Skin

Olya Vvedenskaya, Henri Deda

Xerosis, known as dry skin, affects one-third of the population worldwide, causing itching, irritation, and cracking or peeling. The external skin layer, the stratum corneum, is essential for skin barrier properties, allowing maintaining hydration and regulating trans-epidermal water loss. Here and further, when we talk about skin, we mean the stratum corneum layer. Particular lipids play an essential role in maintaining the skin lipid barrier functions, and lipidome alterations upon application of skin moisturizer can shed the light on the effectiveness of a body lotion. Finally, the skin microbiome has an impact on the condition of the skin. Both parameters, microbiome, and lipidome, are to be analyzed to evaluate the effect of a body lotion on (dry) skin

Link: lipotype.com/xerosis

articles
human, clinical, pharma, skin, cosmetics
11
The Lipidomics Webinar

Composition, Organization & Function of Living Membranes

Ilya Levental

The plasma membrane is the interface between a cell and its environment and is therefore responsible for a myriad of parallel processing tasks that must be tightly regulated to avoid aberrant signaling. To achieve this functional complexity, mammalian cells produce hundreds of lipid species that are actively turned over and trafficked to produce spatial and temporal gradients between cellular compartments. In addition to the plethora of regulatory roles performed by individual lipid molecules, membrane physiology is strictly dependent on the biophysical phenotypes – including membrane fluidity, rigidity, lipid packing, and lateral organization – arising from the collective behaviors of lipids.
Here, we will present the results of several projects that address the lipidomic, biophysical, and functional aspects of mammalian plasma membranes. These projects explore the relationship between membrane organization and cellular function, ultimately demonstrating that membrane phenotypes are central regulators of cell physiology.

Link: lipotype.com/mammalian-cell-membranes

webinars
human, other mammals, organelle, basic science
12
ARTICLE

Lipid Metabolism impacts Remyelination

Olya Vvedenskaya, Henri Deda

Remyelination is a regenerative process that can occur during central nervous system (CNS) damage. In cases like multiple sclerosis or Alzheimer’s disease, remyelination often fails during the progressive phase of a disease. It is essential to understand the details of remyelination and lipid composition remodeling in order to work on the interventions of myelin sheath reconstruction. This study investigates the phagocytes function of clearing cholesterol excess that occurs as a result of a demyelinating injury.

Link: lipotype.com/remyelination

articles
mouse, cells, neuro
13
ARTICLE

T Cell Function & Lipid Metabolism

Henri Deda, Nuala Del Piccolo

The immune system works to protect an individual from external and internal threats and is composed of two complementary subsystems: innate and adaptive immunity. The innate immune system is present at birth; provides a rapid, non-specific response to foreign threats; and is composed of physical barriers like skin and mucus, and specialized cell types including monocytes and neutrophils. The adaptive immune system, on the other hand, learns about threats from the innate immune system and develops specific defenses against them, which can be long-lasting; it is composed of specialized cell types called lymphocytes. T cells are a subset of lymphocytes that – through unique, surface-bound proteins known as T cell receptors (TCRs) – directly recognize and target threat-associated antigens. T cells also communicate with other cells in the adaptive immune system by producing chemical signals known as cytokines. T cell signaling can, like other processes that occur at cellular membranes, be modified by the biophysical properties of membranes. For example, membrane lipid order – a measure of how efficiently lipids can pack together – influences the formation, persistence, and function of signaling platforms. Membrane lipid order depends on membrane composition, environmental temperature, lipid metabolism, and other factors. Overall, this study demonstrates that LXR activation alters lipid metabolism and, through mechanisms that involve membrane lipid order and subsequent modification of cell signaling, immune function in T helper cells. This finding indicates that LXR may be an effective therapeutic target for diseases that involve aberrant T cell signaling, such as cancers and autoimmune disorders.

Link: lipotype.com/t-cell-activation

articles
human, cells, immuno
14
The Lipidomics Webinar

What Have Lipids to Do With the Worst Pandemic Ever?

Kai Simons

Today we are under threat not only from Covid-19 but another even worse pandemic is spreading worldwide and that is obesity, unhealthy weight. This disease does not only cause serious health problems globally but it can also lead to other diseases such as diabetes type 2, cardiovascular disease, liver disease, dementia and cancer. Obesity is driven by the consumption of processed foods, snacks, and soft drinks that are designed so that they even can become addictive. Metabolic parameters can long be maintained in a physiological range. However, once the metabolic overload has overwhelmed the homeostatic control systems, the damage leads to disease.
It is here that the lipids come into play. Lipid homeostasis is central to health. When lipid metabolism becomes dysfunctional, it can turn into a driver for the gamut of obesity-related complications. Amazingly, what is lacking are diagnostic tests that can recognize dysmetabolism before it turns into disease and becomes irreversible. The situation for obesity is like trying to combat Covid without an assay for the virus.
Most excitingly, our studies demonstrate that lipids could provide a means to monitor dysmetabolism. Plasma cholesterol and triglycerides have already proven their worth as useful biomarkers. When you add the complement of lipids in our lipidomes to the analysis, then the differentiation power becomes formidable. The fact that pathological changes occurring in our body organs seem to be mirrored in the blood lipidome could provide the basis for the diagnosis of dysmetabolism. Strangely neglected, lipid metabolism is now emerging as a research area with great potential.

Link: lipotype.com/the-obesity-pandemic

webinars
human, plasma/serum, clinical, biomarker, diet, cvd, diabetes, obesity
15
Nature communications

Chain flexibility of medicinal lipids determines their selective partitioning into lipid droplets

So-Hee Son, Gyuri Park, Junho Lim, Chang Yun Son, Seung Soo Oh, Ju Young Lee

In guiding lipid droplets (LDs) to serve as storage vessels that insulate high-value lipophilic compounds in cells, we demonstrate that chain flexibility of lipids determines their selective migration in intracellular LDs. Focusing on commercially important medicinal lipids with biogenetic similarity but structural dissimilarity, we computationally and experimentally validate that LD remodeling should be differentiated between overproduction of structurally flexible squalene and that of rigid zeaxanthin and β-carotene. In molecular dynamics simulations, worm-like flexible squalene is readily deformed to move through intertwined chains of triacylglycerols in the LD core, whereas rod-like rigid zeaxanthin is trapped on the LD surface due to a high free energy barrier in diffusion. By designing yeast cells with either much larger LDs or with a greater number of LDs, we observe that intracellular storage of squalene significantly increases with LD volume expansion, but that of zeaxanthin and β-carotene is enhanced through LD surface broadening; as visually evidenced, the outcomes represent internal penetration of squalene and surface localization of zeaxanthin and β-carotene. Our study shows the computational and experimental validation of selective lipid migration into a phase-separated organelle and reveals LD dynamics and functionalization.

Link: doi.org/10.1038/s41467-022-31400-6

publications
cells, yeast, basic science
16
scientific reports

A set of gene knockouts as a resource for global lipidomic changes

Aleksandra Spiegel, Chris Lauber, Mandy Bachmann, Anne-Kristin Heninger, Christian Klose, Kai Simons, Mihail Sarov, Mathias J Gerl

Enzyme specificity in lipid metabolic pathways often remains unresolved at the lipid species level, which is needed to link lipidomic molecular phenotypes with their protein counterparts to construct functional pathway maps. We created lipidomic profiles of 23 gene knockouts in a proof-of-concept study based on a CRISPR/Cas9 knockout screen in mammalian cells. This results in a lipidomic resource across 24 lipid classes. We highlight lipid species phenotypes of multiple knockout cell lines compared to a control, created by targeting the human safe-harbor locus AAVS1 using up to 1228 lipid species and subspecies, charting lipid metabolism at the molecular level. Lipid species changes are found in all knockout cell lines, however, some are most apparent on the lipid class level (e.g., SGMS1 and CEPT1), while others are most apparent on the fatty acid level (e.g., DECR2 and ACOT7). We find lipidomic phenotypes to be reproducible across different clones of the same knockout and we observed similar phenotypes when two enzymes that catalyze subsequent steps of the long-chain fatty acid elongation cycle were targeted.

Link: doi.org/10.1038/s41598-022-14690-0

publications
human, cells, basic science
17
EMBO reports

Metabolic routing maintains the unique fatty acid composition of phosphoinositides

Yeun Ju Kim, Nivedita Sengupta, Mira Sohn, Amrita Mandal, Joshua G Pemberton, Uimook Choi, Tamas Balla

Phosphoinositide lipids (PPIn) are enriched in stearic- and arachidonic acids (38:4) but how this enrichment is established and maintained during phospholipase C (PLC) activation is unknown. Here we show that the metabolic fate of newly synthesized phosphatidic acid (PA), the lipid precursor of phosphatidylinositol (PI), is influenced by the fatty acyl-CoA used with preferential routing of the arachidonoyl-enriched species toward PI synthesis. Furthermore, during agonist stimulation the unsaturated forms of PI(4,5P)2 are replenished significantly faster than the more saturated ones, suggesting a favored recycling of the unsaturated forms of the PLC-generated hydrolytic products. Cytidine diphosphate diacylglycerol synthase 2 (CDS2) but not CDS1 was found to contribute to increased PI resynthesis during PLC activation. Lastly, while the lipid transfer protein, Nir2 is found to contribute to rapid PPIn resynthesis during PLC activation, the faster re-synthesis of the 38:4 species does not depend on Nir2. Therefore, the fatty acid side-chain composition of the lipid precursors used for PI synthesis is an important determinant of their metabolic fates, which also contributes to the maintenance of the unique fatty acid profile of PPIn lipids.

Link: doi.org/10.15252/embr.202154532

publications
human, cells, basic science
18
npj Parkinson's disease

Lipase regulation of cellular fatty acid homeostasis as a Parkinson’s disease therapeutic strategy

Saranna Fanning, Haley Cirka, Jennifer L Thies, Jooyoung Jeong, Sarah M Niemi, Joon Yoon, Gary P H Ho, Julian A Pacheco, Ulf Dettmer, Lei Liu, Clary B Clish, Kevin J Hodgetts, John N Hutchinson, Christina R Muratore, Guy A Caldwell, Kim A Caldwell, Dennis Selkoe

Synucleinopathy (Parkinson’s disease (PD); Lewy body dementia) disease-modifying treatments represent a huge unmet medical need. Although the PD-causing protein α-synuclein (αS) interacts with lipids and fatty acids (FA) physiologically and pathologically, targeting FA homeostasis for therapeutics is in its infancy. We identified the PD-relevant target stearoyl-coA desaturase: inhibiting monounsaturated FA synthesis reversed PD phenotypes. However, lipid degradation also generates FA pools. Here, we identify the rate-limiting lipase enzyme, LIPE, as a candidate target. Decreasing LIPE in human neural cells reduced αS inclusions. Patient αS triplication vs. corrected neurons had increased pSer129 and insoluble αS and decreased αS tetramer:monomer ratios. LIPE inhibition rescued all these and the abnormal unfolded protein response. LIPE inhibitors decreased pSer129 and restored tetramer:monomer equilibrium in αS E46K-expressing human neurons. LIPE reduction in vivo alleviated αS-induced dopaminergic neurodegeneration in Caenorhabditis elegans. Co-regulating FA synthesis and degradation proved additive in rescuing PD phenotypes, signifying co-targeting as a therapeutic strategy.

Link: doi.org/10.1038/s41531-022-00335-6

publications
human, cells, neuro, nematoda
19
Genetics

Fine tuning Acetyl-CoA Carboxylase 1 activity through localization: Functional genomics reveal a role for the lysine acetyltransferase NuA4 and sphingolipid metabolism in regulating Acc1 activity and localization

Trang Pham, Elizabeth Walden, Sylvain Huard, John Pezacki, Morgan D Fullerton, Kristin Baetz

Acetyl-CoA Carboxylase 1 (Acc1) catalyzes the conversion of acetyl-CoA to malonyl-CoA, the committed step of de novo fatty acid synthesis. As a master-regulator of lipid synthesis, Acc1 has been proposed to be a therapeutic target for numerous metabolic diseases. We have shown that Acc1 activity is reduced in the absence of the lysine acetyltransferase NuA4 in Saccharomyces cerevisiae. This change in Acc1 activity is correlated with a change in localization. In wild-type cells Acc1 is localized throughout the cytoplasm in small punctate and rod-like structures. However, in NuA4 mutants, Acc1 localization becomes diffuse. To uncover mechanisms regulating Acc1 localization we performed a microscopy screen to identify other deletion mutants that impact Acc1 localization and then measured Acc1 activity in these mutants through chemical genetics and biochemical assays. Three phenotypes were identified. Mutants with hyper-active Acc1 form one or two rod-like structures centrally within the cytoplasm, mutants with mid-low Acc1 activity displayed diffuse Acc1, while the mutants with the lowest Acc1 activity (hypomorphs) formed thick rod-like Acc1 structures at the periphery of the cell. All the Acc1 hypomorphic mutants were implicated in sphingolipid metabolism or very-long chain fatty acid elongation and in common, their deletion causes an accumulation of palmitoyl-CoA. Through exogenous lipid treatments, enzyme inhibitors and genetics, we determined that increasing palmitoyl-CoA levels inhibits Acc1 activity and remodels Acc1 localization. Together this study suggests yeast cells have developed a dynamic feed-back mechanism in which downstream products of Acc1 can fine-tune the rate of fatty acid synthesis.

Link: doi.org/10.1093/genetics/iyac086

publications
cells, yeast, basic science
20
ARTICLE

What is Multiomics?

Henri Deda, Nuala Del Piccolo

The production and analysis of so-called omics datasets – such as the genes, lipids, proteins, metabolites, or microbes – has rapidly gained popularity in biomedical research. Individual analysis of an omics dataset can identify links between the characterized feature and a specific biological phenomena. Multiomics is the integrated analysis of multiple omics datasets, and can identify mechanisms of action, biomarkers, networks, pathways, and other relationships present in physiological and pathological processes. Multiomics analyses have been used to characterize, monitor, and predict many disease states. The following case studies describe recent multiomics-based studies of four common diseases – namely, Alzheimer’s disease, cardiovascular disease, type I diabetes, and ovarian cancer – in which inclusion of lipidome data helped reveal something new about well-studied diseases.

Link: lipotype.com/what-is-multiomics

articles
human, organ/tissue, mouse, plasma/serum, clinical, other mammals, biomarker, cells, csf, neuro, cvd, diabetes, cancer
21
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

Lifespan Extension of Podospora anserina Mic60-Subcomplex Mutants Depends on Cardiolipin Remodeling

Lisa-Marie Marschall, Verena Warnsmann, Anja C Meeßen, Timo Löser, Heinz D Osiewacz

Function of mitochondria largely depends on a characteristic ultrastructure with typical invaginations, namely the cristae of the inner mitochondrial membrane. The mitochondrial signature phospholipid cardiolipin (CL), the F1Fo-ATP-synthase, and the ‘mitochondrial contact site and cristae organizing system’ (MICOS) complex are involved in this process. Previous studies with Podospora anserina demonstrated that manipulation of MICOS leads to altered cristae structure and prolongs lifespan. While longevity of Mic10-subcomplex mutants is induced by mitohormesis, the underlying mechanism in the Mic60-subcomplex deletion mutants was unclear. Since several studies indicated a connection between MICOS and phospholipid composition, we now analyzed the impact of MICOS on mitochondrial phospholipid metabolism. Data from lipidomic analysis identified alterations in phospholipid profile and acyl composition of CL in Mic60-subcomplex mutants. These changes appear to have beneficial effects on membrane properties and promote longevity. Impairments of CL remodeling in a PaMIC60 ablated mutant lead to a complete abrogation of longevity. This effect is reversed by supplementation of the growth medium with linoleic acid, a fatty acid which allows the formation of tetra-octadecanoyl CL. In the PaMic60 deletion mutant, this CL species appears to lead to longevity. Overall, our data demonstrate a tight connection between MICOS, the regulation of mitochondrial phospholipid homeostasis, and aging of P. anserina.

Link: doi.org/10.3390/ijms23094741

publications
aging, organelle, other fungi
22
Journal of Cell Biology

Regulated targeting of the monotopic hairpin membrane protein Erg1 requires the GET pathway

Ákos Farkas, Henning Urlaub, Katherine E Bohnsack, Blanche Schwappach

The guided entry of tail-anchored proteins (GET) pathway targets C-terminally anchored transmembrane proteins and protects cells from lipotoxicity. Here, we reveal perturbed ergosterol production in ∆get3 cells and demonstrate the sensitivity of GET pathway mutants to the sterol synthesis inhibiting drug terbinafine. Our data uncover a key enzyme of sterol synthesis, the hairpin membrane protein squalene monooxygenase (Erg1), as a non-canonical GET pathway client, thus rationalizing the lipotoxicity phenotypes of GET pathway mutants. Get3 recognizes the hairpin targeting element of Erg1 via its classical client-binding pocket. Intriguingly, we find that the GET pathway is especially important for the acute upregulation of Erg1 induced by low sterol conditions. We further identify several other proteins anchored to the endoplasmic reticulum (ER) membrane exclusively via a hairpin as putative clients of the GET pathway. Our findings emphasize the necessity of dedicated targeting pathways for high-efficiency targeting of particular clients during dynamic cellular adaptation and highlight hairpin proteins as a potential novel class of GET clients.

Link: doi.org/10.1083/jcb.202201036

publications
cells, yeast, basic science
23
The Lipidomics Webinar

Shotgun Lipidomics of Tissue Biopsies

Andrej Shevchenko

Liquid biopsies (e.g. plasma or serum) is an available clinical resource extensively exploited by lipidomics. However, plasma lipidome changes reflect the diseases progressing elsewhere in different organs only indirectly. The direct analysis of tissue biopsies could be in a better position to elucidate molecular details of pathophysiological mechanisms.
Biopsies lipidomics requires careful standardization, the collection of abundant meta- and histological data together with robust normalization of lipid abundances. By providing absolute (molar) abundances of lipid species in whole biopsies, it creates a generic and expandable lipidomics resource. Furthermore, shotgun lipidomics could address spatial distribution of lipids by analyzing histological features isolated by laser capture microdissection (LCM). Combining the material from many similar features increases the lipidome coverage and enables to complement lipidomics with proteomics to confirm the dissection specificity by quantifying histologically specific markers.
Systematic shotgun analysis of whole and LCM-dissected liver, colon and pancreas biopsies suggested that, in general, tissues tend to preserve their lipid composition even when histological analyses indicate profound changes in their morphology. Significant lipidome perturbation are specific to a few individual species within spatially defined zones and offer new and often unexpected look at the pathophysiological role of lipid metabolism.

Link: lipotype.com/shotgun-lipidomics-of-tissue-biopsies

webinars
human, organ/tissue, plasma/serum, clinical, biomarker, obesity
24
eLife

Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes

Albert Pérez-Martí, Suresh Ramakrishnan, Jiayi Li, Aurelien Dugourd, Martijn R Molenaar, Luigi R De La Motte, Kelli Grand, Anis Mansouri, Mélanie Parisot, Soeren S Lienkamp, Julio Saez-Rodriguez, Matias Simons

In diabetic patients, dyslipidemia frequently contributes to organ damage such as diabetic kidney disease (DKD). Dyslipidemia is associated with both excessive deposition of triacylglycerol (TAG) in lipid droplets (LDs) and lipotoxicity. Yet, it is unclear how these two effects correlate with each other in the kidney and how they are influenced by dietary patterns. By using a diabetes mouse model, we find here that high-fat diet enriched in the monounsaturated oleic acid (OA) caused more lipid storage in LDs in renal proximal tubular cells (PTCs) but less tubular damage than a corresponding butter diet with the saturated palmitic acid (PA). This effect was particularly evident in S2/S3 but not S1 segments of the proximal tubule. Combining transcriptomics, lipidomics, and functional studies, we identify endoplasmic reticulum (ER) stress as the main cause of PA-induced PTC injury. Mechanistically, ER stress is caused by elevated levels of saturated TAG precursors, reduced LD formation, and, consequently, higher membrane order in the ER. Simultaneous addition of OA rescues the cytotoxic effects by normalizing membrane order and increasing both TAG and LD formation. Our study thus emphasizes the importance of monounsaturated fatty acids for the dietary management of DKD by preventing lipid bilayer stress in the ER and promoting TAG and LD formation in PTCs.

Link: doi.org/10.7554/eLife.74391

publications
organ/tissue, mouse, cells, diet, diabetes
25
Article

Multiomics Analysis of Cancer Chemotherapy Sensitivity

Henri Deda, Nuala Del Piccolo

Ovarian cancers can be classified into four subtypes – serous, mucinous, endometrioid, and clear-cell – based on their histology. These subtypes exhibit varying sensitivity to platinum-based chemotherapy and seem to incorporate different amounts of lipids into their cells. The four ovarian cancer subtypes – serous, mucinous, endometrioid, and clear-cell – were modeled using cell lines, murine models, fixed patient tissue samples, and data from The Cancer Genome Atlas. These models were characterized via viability, chemosensitivity, lipidomic, and transcriptomic assays. In both ovarian cancer cell lines and patient samples, LDLR expression was high in endometrioid and clear-cell and low in serous and mucinous ovarian cancers. Additionally, in an in vitro assay, serous cells were more sensitive than clear-cell and endometrioid cells to cisplatin. Consistent with this observation, increasing LDLR expression in serous cells and knocking down expression in clear-cell and endometrioid cells respectively reduced and enhanced chemo-sensitivity. Overall, this study revealed that overexpression of LDLR reduces sensitivity to platinum-based therapy in ovarian cancer cell lines and murine models.

Link: lipotype.com/multiomics-of-cancer-chemotherapy-sensitivity

articles
human, organ/tissue, mouse, cells, cancer
26
Journal of Biological Chemistry

microRNA-27b regulates hepatic lipase enzyme LIPC and reduces triglyceride degradation during hepatitis C virus infection

Geneviève F Desrochers, Roxana Filip, Micheal Bastianelli, Tiffany Stern, John Paul Pezacki

MicroRNAs are short, non-coding RNAs that negatively and specifically regulate protein expression, the cumulative effects of which can result in broad changes to cell systems and architecture. The microRNA miR-27b is known to regulate lipid-regulatory pathways in the human liver and is also induced by the hepatitis C virus (HCV). However, miR-27b’s functional targets are not well established. Herein, an activity-based protein profiling method using a serine hydrolase probe, coupled with stable isotope labelling and mass spectrometry identified direct and indirect targets of miR-27b. The hepatic lipase LIPC stood out as both highly dependent on miR-27b and as a major modulator of lipid pathway misregulation. Modulation of miR-27b using both exogenous microRNA mimics and inhibitors demonstrated that transcription factors Jun, PPARα, and HNF4α all of which also influenced LIPC levels and activity, are regulated by miR-27b. LIPC was furthermore shown to affect the progress of the life cycle of HCV, and to decrease levels of intracellular triglycerides, upon which HCV is known to depend. In summary, this work has demonstrated that miR-27b mediates HCV infection by downregulating LIPC, thereby reducing triglyceride degradation, which in turn increases cellular lipid levels.

Link: doi.org/10.1016/j.jbc.2022.101983

publications
human, cells, basic science
27
Life Science Alliance

Tricalbin proteins regulate plasma membrane phospholipid homeostasis

Ffion B Thomas, Deike J Omnus, Jakob M Bader, Gary HC Chung, Nozomu Kono, Christopher J Stefan

The evolutionarily conserved extended synaptotagmin (E-Syt) proteins are calcium-activated lipid transfer proteins that function at contacts between the ER and plasma membrane (ER-PM contacts). However, roles of the E-Syt family members in PM lipid organisation remain incomplete. Among the E-Syt family, the yeast tricalbin (Tcb) proteins are essential for PM integrity upon heat stress, but it is not known how they contribute to PM maintenance. Using quantitative lipidomics and microscopy, we find that the Tcb proteins regulate phosphatidylserine homeostasis at the PM. Moreover, upon heat-induced membrane stress, Tcb3 co-localises with the PM protein Sfk1 that is implicated in PM phospholipid asymmetry and integrity. The Tcb proteins also control the PM targeting of the known phosphatidylserine effector Pkc1 upon heat-induced stress. Phosphatidylserine has evolutionarily conserved roles in PM organisation, integrity, and repair. We propose that phospholipid regulation is an ancient essential function of E-Syt family members required for PM integrity.

Link: doi.org/10.26508/lsa.202201430

publications
cells, yeast, basic science
28
The Lipidomics Webinar

How to Yeast Lipidomics Research

Christian Klose

The yeast Saccharomyces cerevisiae is a powerful model system for cell and molecular biology research. This is mostly due to the availability of simple and straightforward genetic and molecular tools and methods to manipulate almost any cell biological process.
Lipidomics has become an indispensable method for the quantitative assessment of lipid metabolism and membrane biology in studies employing yeast as an experimental system. Here we show how lipidomics is applied to investigate the influence of a variety of commonly used growth conditions on the yeast lipidome, including glycerophospholipids, triglycerides, ergosterol as well as complex sphingolipids, establishing a baseline for future lipidomic experiments in yeast.
Based on this work, we review acyl chain remodeling as a fundamental aspect of membrane biology, the roles of lipids in the unfolded protein response (UPR) in both endoplasmic reticulum (ER) and mitochondria, as well as the lipid-based regulation of key biological process like control of cell size and growth rate. These studies provide mechanistic insights into the amazing diversity of lipid functions in essential cellular processes conserved throughout the eukaryotic domain of life.

Link: lipotype.com/how-to-yeast-lipidomics-research

webinars
cells, organelle, yeast, basic science
29
EMBO Molecular Medicine

AAV-delivered diacylglycerol kinase DGKk achieves long-term rescue of fragile X syndrome mouse model

Karima Habbas, Oktay Cakil, Boglárka Zámbó, Ricardos Tabet, Fabrice Riet, Doulaye Dembele, Jean-Louis Mandel, Michaël Hocquemiller, Ralph Laufer, Françoise Piguet, Hervé Moine

Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. FXS results from the lack of the RNA-binding protein FMRP and is associated with the deregulation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk), a main mRNA target of FMRP in cortical neurons and a master regulator of lipid signaling, is downregulated in the absence of FMRP in the brain of Fmr1-KO mouse model. Here we show that adeno-associated viral vector delivery of a modified and FMRP-independent form of DGKk corrects abnormal cerebral diacylglycerol/phosphatidic acid homeostasis and FXS-relevant behavioral phenotypes in the Fmr1-KO mouse. Our data suggest that DGKk is an important factor in FXS pathogenesis and provide preclinical proof of concept that its replacement could be a viable therapeutic strategy in FXS.

Link: doi.org/10.15252/emmm.202114649

publications
organ/tissue, mouse, neuro
30
MDPI Molecules

Shotgun Lipidomic Analysis for Differentiation of Niche Cold Pressed Oils

Hanna Nikolaichuk, Kacper Przykaza, Anna Kozub, Magdalena Montowska, Grażyna Wójcicka, Jolanta Tomaszewska-Gras, Emilia Fornal

The fast-growing food industry is bringing significant number of new products to the market. To protect consumers’ health and rights, it is crucial that food control laboratories are able to ensure reliable quality testing, including product authentication and detection of adulterations. In our study, we applied a fast and eco-friendly method based on shotgun-lipidomic mass spectrometry for the authentication of niche edible oils. Comprehensive lipid profiles of camelina (CA), flax (FL) and hemp (HP) seed oils were obtained. With the aid of principal component analysis (PCA), it was possible to detect and distinguish each of them based on their lipid profiles. Lipidomic markers characteristic ofthe oils were also identified, which can be used as targets and expedite development of new multiplexed testing methods.

Link: doi.org/10.3390/molecules27061848

publications
diet, oil, plants
31
Scientific reports

Alteration of barrier properties, stratum corneum ceramides and microbiome composition in response to lotion application on cosmetic dry skin

Barry Murphy, Sally Grimshaw, Michael Hoptroff, Sarah Paterson, David Arnold, Andrew Cawley, Suzanne E Adams, Francesco Falciani, Tony Dadd, Richard Eccles, Alex Mitchell, William F Lathrop, Diana Marrero, Galina Yarova, Ana Villa, John S Bajor, Lin Feng, Dawn Mihalov, Andrew E Mayes

Xerosis, commonly referred to as dry skin, is a common dermatological condition affecting almost a third of the population. Successful treatment of the condition traditionally involves the application of cosmetic products facilitating the moisturisation of the skin with a range of ingredients including glycerol and fatty acids. While the effectiveness of these treatments is not in question, limited information exists on the impact on the skin microbiome following use of these products and the improvement in skin hydration. Here, we describe improvements in skin barrier properties together with increased levels of cholesterol, ceramides and long-chain fatty acids following application of Body Lotion. Concomitant alterations in the skin microbiome are also seen via 16S rRNA metataxonomics, in combination with both traditional and novel informatics analysis. Following 5 weeks of lotion use, beneficial skin bacteria are increased, with improvements in microbiome functional potential, and increases in pathways associated with biosynthesis of multiple long chain fatty acids.

Link: doi.org/10.1038/s41598-022-09231-8

publications
human, skin, cosmetics
32
Article

Cardiolipin Synthesis & Protein Import During mtUPR

Henri Deda, Nuala Del Piccolo

Like the cell’s unfolded protein response, the mitochondrial unfolded protein response (mtUPR) is a protective mechanism triggered by organelle dysfunction – often due to mutations, aging, exposure to toxins, or other stress. During mtUPR, metabolism, gene expression, and/or other processes are modified to protect the organelle – and especially oxidative phosphorylation – and the cell. Kinetic analyses in isolated mitochondria showed that protein import increased in the early phase of mtUPR (2-10 hours after induction) compared to wild-type yeast. In the late phase of mtUPR (20 hours after induction), protein import decreased. In search of a mechanism underlying these observations, mitochondrial lipid composition was characterized. Membrane lipid composition is known to modulate the function of membrane proteins – like those involved in protein import. These lipidomic data identified increases in the abundance of cardiolipin and its metabolic precursor and a decrease in cardiolipin acyl chain length during the early phase of mtUPR. Overall, this study identified and characterized two phases of mtUPR. In the early phase of mtUPR, protein import increased, and this was accompanied by cardiolipin synthesis and remodeling. In the late phase of mtUPR, protein import decreased.

Link: lipotype.com/mitochondrial-unfolded-protein-response

articles
organelle, yeast, basic science
33
Article

Chain Length Impacts Membrane Fluidity

Henri Deda, Nuala Del Piccolo

Cellular membranes are heterogeneous, flexible, 2D structures composed of lipids, proteins, and carbohydrates. They are the site of many essential biological functions, including signal transduction, nutrient/waste transport, and energy generation. To optimize membranes for each of these varied functions, cells tune membrane biophysical properties, such as structure, composition, and fluidity. In eukaryotes, the glycerophospholipid phosphatidylcholine (PC) is abundant in the membrane – it can account for over 50% of membrane lipids – and has functional roles in signal transduction and metabolism. To probe how yeast adapt to the lack of PC, whole-cell lipids were isolated and characterized via mass spectrometry-based shotgun lipidomics and thin layer chromatography. Overall, this study demonstrates that yeast can adapt to the absence of PC by reducing the activity of the enzyme Acc1, thus decreasing acyl chain length and restoring membrane fluidity.

Link: lipotype.com/fatty-acid-chain-length-membrane-fluidity

articles
cells, organelle, yeast, basic science
34
PLOS Biology

Lipidomic risk scores are independent of polygenic risk scores and can predict incidence of diabetes and cardiovascular disease in a large population cohort

Chris Lauber, Mathias J Gerl, Christian Klose, Filip Ottosson, Olle Melander, Kai Simons

Type 2 diabetes (T2D) and cardiovascular disease (CVD) represent significant disease burdens for most societies and susceptibility to these diseases is strongly influenced by diet and lifestyle. Physiological changes associated with T2D or CVD, such has high blood pressure and cholesterol and glucose levels in the blood, are often apparent prior to disease incidence. Here we integrated genetics, lipidomics, and standard clinical diagnostics to assess future T2D and CVD risk for 4,067 participants from a large prospective population-based cohort, the Malmö Diet and Cancer-Cardiovascular Cohort. By training Ridge regression-based machine learning models on the measurements obtained at baseline when the individuals were healthy, we computed several risk scores for T2D and CVD incidence during up to 23 years of follow-up. We used these scores to stratify the participants into risk groups and found that a lipidomics risk score based on the quantification of 184 plasma lipid concentrations resulted in a 168% and 84% increase of the incidence rate in the highest risk group and a 77% and 53% decrease of the incidence rate in lowest risk group for T2D and CVD, respectively, compared to the average case rates of 13.8% and 22.0%. Notably, lipidomic risk correlated only marginally with polygenic risk, indicating that the lipidome and genetic variants may constitute largely independent risk factors for T2D and CVD. Risk stratification was further improved by adding standard clinical variables to the model, resulting in a case rate of 51.0% and 53.3% in the highest risk group for T2D and CVD, respectively. The participants in the highest risk group showed significantly altered lipidome compositions affecting 167 and 157 lipid species for T2D and CVD, respectively. Our results demonstrated that a subset of individuals at high risk for developing T2D or CVD can be identified years before disease incidence. The lipidomic risk, which is derived from only one single mass spectrometric measurement that is cheap and fast, is informative and could extend traditional risk assessment based on clinical assays.

Link: doi.org/10.1371/journal.pbio.3001561

publications
human, plasma/serum, clinical, biomarker, cvd, diabetes
35
Brain

Sphingolipid changes in Parkinson L444P GBA mutation fibroblasts promote α-synuclein aggregation

Céline Galvagnion, Frederik Ravnkilde Marlet, Silvia Cerri, Anthony H V Schapira, Fabio Blandini, Donato A Di Monte

Intraneuronal accumulation of aggregated α-synuclein is a pathological hallmark of Parkinson’s disease. Therefore, mechanisms capable of promoting α-synuclein deposition bear important pathogenetic implications. Mutations of the glucocerebrosidase 1 (GBA) gene represent a prevalent Parkinson’s disease risk factor. They are associated with loss of activity of a key enzyme involved in lipid metabolism, glucocerebrosidase, supporting a mechanistic relationship between abnormal α-synuclein–lipid interactions and the development of Parkinson pathology.

In this study, the lipid membrane composition of fibroblasts isolated from control subjects, patients with idiopathic Parkinson’s disease and Parkinson’s disease patients carrying the L444P GBA mutation (PD-GBA) was assayed using shotgun lipidomics.

The lipid profile of PD-GBA fibroblasts differed significantly from that of control and idiopathic Parkinson’s disease cells. It was characterized by an overall increase in sphingolipid levels. It also featured a significant increase in the proportion of ceramide, sphingomyelin and hexosylceramide molecules with shorter chain length and a decrease in the percentage of longer-chain sphingolipids. The extent of this shift was correlated to the degree of reduction of fibroblast glucocerebrosidase activity. Lipid extracts from control and PD-GBA fibroblasts were added to recombinant α-synuclein solutions. The kinetics of α-synuclein aggregation were significantly accelerated after addition of PD-GBA extracts as compared to control samples. Amyloid fibrils collected at the end of these incubations contained lipids, indicating α-synuclein–lipid co-assembly. Lipids extracted from α-synuclein fibrils were also analysed by shotgun lipidomics. Data revealed that the lipid content of these fibrils was significantly enriched by shorter-chain sphingolipids. In a final set of experiments, control and PD-GBA fibroblasts were incubated in the presence of the small molecule chaperone ambroxol. This treatment restored glucocerebrosidase activity and sphingolipid levels and composition of PD-GBA cells. It also reversed the pro-aggregation effect that lipid extracts from PD-GBA fibroblasts had on α-synuclein.

Taken together, the findings of this study indicate that the L444P GBA mutation and consequent enzymatic loss are associated with a distinctly altered membrane lipid profile that provides a biological fingerprint of this mutation in Parkinson fibroblasts. This altered lipid profile could also be an indicator of increased risk for α-synuclein aggregate pathology.

Link: doi.org/10.1093/brain/awab371

publications
human, cells, organelle, neuro
36
The Lipidomics Webinar

How to make sense of lipidomics data?

Mathias J Gerl

Lipidomics provide unprecedented phenotypic details by accumulating large amounts of data. While these are potentially of great value, the amount and complexity of the data can be intimidating initially. This webinar is designed to show the basics of lipidomics analysis. It will cover the characteristics of the datasets, e.g. their lipid substructure and multicollinearity, and how to deal with them. We will go through data preparation, how to calculate new features and how to use principal component analysis as a first impression. Then we will focus on univariate and correlation analysis combined with enrichment analysis.

Link: lipotype.com/how-to-make-sense-of-lipidomics-data

webinars
method
37
Frontiers in Cell and Developmental Biology

Sterol Metabolism Differentially Contributes to Maintenance and Exit of Quiescence

Carlotta Peselj, Mahsa Ebrahimi, Filomena Broeskamp, Simon Prokisch, Lukas Habernig, Irene Alvarez-Guerra, Verena Kohler, F-Nora Vögtle, Sabrina Büttner

Nutrient starvation initiates cell cycle exit and entry into quiescence, a reversible, non-proliferative state characterized by stress tolerance, longevity and large-scale remodeling of subcellular structures. Depending on the nature of the depleted nutrient, yeast cells are assumed to enter heterogeneous quiescent states with unique but mostly unexplored characteristics. Here, we show that storage and consumption of neutral lipids in lipid droplets (LDs) differentially impacts the regulation of quiescence driven by glucose or phosphate starvation. Upon prolonged glucose exhaustion, LDs were degraded in the vacuole via Atg1-dependent lipophagy. In contrast, yeast cells entering quiescence due to phosphate exhaustion massively over-accumulated LDs that clustered at the vacuolar surface but were not engulfed via lipophagy. Excessive LD biogenesis required contact formation between the endoplasmic reticulum and the vacuole at nucleus-vacuole junctions and was accompanied by a shift of the cellular lipid profile from membrane towards storage lipids, driven by a transcriptional upregulation of enzymes generating neutral lipids, in particular sterol esters. Importantly, sterol ester biogenesis was critical for long-term survival of phosphate-exhausted cells and supported rapid quiescence exit upon nutrient replenishment, but was dispensable for survival and regrowth of glucose-exhausted cells. Instead, these cells relied on de novo synthesis of sterols and fatty acids for quiescence exit and regrowth. Phosphate-exhausted cells efficiently mobilized storage lipids to support several rounds of cell division even in presence of inhibitors of fatty acid and sterol biosynthesis. In sum, our results show that neutral lipid biosynthesis and mobilization to support quiescence maintenance and exit is tailored to the respective nutrient scarcity.

Link: doi.org/10.3389/fcell.2022.788472

publications
cells, yeast, basic science
38
International Journal of Cosmetic Science

Changes in levels of omega-O-acylceramides and related processing enzymes of sun-exposed and sun-protected facial stratum corneum in differently pigmented ethnic groups

Anthony V Rawlings, Rotraut Schoop, Christian Klose, Jean-Marc Monneuse, Beverley Summers, Rainer Voegeli

We report on the differences in ceramide composition and levels of omega-O-acylceramide processing enzymes of sun-exposed and sun-protected facial stratum corneum (SC) among Albino African, Black African and Caucasian women living in South Africa. Tape strippings were taken from the sun-exposed cheek and the sun-protected postauricular site (PA). In two subsets proteomic (n=18) and lipidomic (n=24) analysis were performed using mass-spectrometry-based shotgun platforms. No significant differences in total ceramide levels or ceramide subtypes were found between the Black African and Caucasian women in either the cheek or PA samples. Compared to the other two groups the levels of total ceramide as well as selected omega-O-acylceramide species were increased in Albino Africans. On the cheek, ceramide (CER) EOS, EOH along with CER AS were increased relative to the Caucasian women, while CER EOP and EOdS were elevated relative to the Black African women. Moreover, on the PA site CER EOP and EOdS were elevated compared with the Black African women and CER EOdS in Caucasians. Decreases in mass levels of 12R-LOX and eLOX3 were observed on cheeks compared with the PA sites in all ethnic groups. On the PA sites 12R-LOX was particularly lower in the Albino Africans compared with the Black African and Caucasian women. On the cheeks mass levels of SDR9C7 was also lower in the Albino Africans. The mass levels of the ceramides were similar between Black African and Caucasian women. However, elevated total ceramides and excessively elevated selected omega-O-acylceramides were apparent in the Albino African women. The findings in the Albino women were unexpected as these participants suffer from impaired skin barrier function. However, the elevated levels omega-O-acylceramides can contribute to barrier insufficiency by directly impacting SC lipid phase behaviour and/or secondly elevated omega-O-acylceramide levels may indicate a reduced attachment of ceramides to the corneocyte lipid envelope and reduced corneocyte maturation that can also impair the barrier. Indeed, differences in the mass levels of omega-O-acylceramide processing enzymes were observed for 12R-LOX and SDR9C7 for the Albino Africans. This indicates a corneocyte lipid scaffold disorder in the Albino African women.

Link: doi.org/10.1111/ics.12765

publications
human, skin, cosmetics
39
Article

Anorexia, Refeeding & Lipid Metabolism

Henri Deda, Nuala Del Piccolo

Anorexia nervosa, an eating disorder, manifests itself as self-starvation, excessive weight loss and a distorted body image. Due to chronic undernutrition, anorexia patients may also experience changes in the body’s metabolism and endocrine system. Refeeding therapy – in which anorexia patients are hospitalized and fed a prescribed diet to induce weight gain – is the most successful current therapy. However, the optimal number of calories, nutritional content, and pacing of this therapy remain largely unexplored. The plasma lipid profile has recently emerged as a marker of metabolic health. Preliminary evidence suggests that the plasma lipidome may also provide insight on the metabolic health of patients with anorexia before, during, and/or after refeeding therapy.

Link: lipotype.com/lipid-metabolism-in-anorexia-refeeding-therapy

articles
human, plasma/serum, clinical, diet, neuro, obesity
40
Cell

Fundamental behaviors emerge from simulations of a living minimal cell

Zane R Thornburg, David M Bianchi, Troy A Brier, Benjamin R Gilbert, Tyler M Earnest, Marcelo C R Melo, Nataliya Safronova, James P Sáenz, András T Cook, Kim S Wise, Clyde A Hutchison III, Hamilton O Smith, John I Glass, Zaida Luthey-Schulten

We present a whole-cell fully dynamical kinetic model (WCM) of JCVI-syn3A, a minimal cell with a reduced genome of 493 genes that has retained few regulatory proteins or small RNAs. Cryo-electron tomograms provide the cell geometry and ribosome distributions. Time-dependent behaviors of concentrations and reaction fluxes from stochastic-deterministic simulations over a cell cycle reveal how the cell balances demands of its metabolism, genetic information processes, and growth, and offer insight into the principles of life for this minimal cell. The energy economy of each process including active transport of amino acids, nucleosides, and ions is analyzed. WCM reveals how emergent imbalances lead to slowdowns in the rates of transcription and translation. Integration of experimental data is critical in building a kinetic model from which emerges a genome-wide distribution of mRNA half-lives, multiple DNA replication events that can be compared to qPCR results, and the experimentally observed doubling behavior.

Link: doi.org/10.1016/j.cell.2021.12.025

publications
cells, bacteria, basic science
41
Article

Insulin Sensitivity & Circadian Lipid Metabolism

Henri Deda, Nuala Del Piccolo

Lipid metabolism is regulated by circadian rhythms and therefore altered in people with atypical sleeping cycles, including those who work night shifts. Unfortunately, changes in lipid metabolism are also linked to metabolic diseases, including diabetes. Insulin sensitivity, a measure of the body’s responsiveness to insulin, is linked to lipid metabolism and reduced in type II diabetes. Here we show how the molecular mechanisms that contribute to insulin sensitivity are impacted by meal timing and composition – two external factors that influence circadian rhythms.

Link: lipotype.com/circadian-lipid-metabolism-and-insulin-sensitivity

articles
human, organ/tissue, plasma/serum, clinical, diet, diabetes
42
The Lipidomics Webinar

Why Population Health Studies Must Apply Lipidomics

Christian Klose

In the past century, population health studies have proven a powerful approach to reveal connections between diseases and their risk factors in epidemiology. We have now moved into an era, in which population health studies frequently rely on omics technologies (such as genomics, transcriptomics, metabolomics, and lipidomics) to identify disease risk factors at the molecular level.
Omics technologies provide unprecedented phenotypic details by accumulating vast amounts of data. While these are potentially of enormous value, biomarker identification studies benefit only if the data are of high quality and reliably reproducible. Fortunately, shotgun lipidomics fulfills these requirements and can therefore successfully be applied in biomarker identification studies covering indications such as obesity, diabetes, cardiovascular, and neurodegenerative diseases. Most importantly, human plasma lipidomics seems to reflect the body metabolism and has the potential to fill a hole in clinical diagnostics that lacks methods to measure metabolism.
Besides revealing promising potential multiparametric diagnostic and prognostic markers, large population health studies have proven that lipidomics is a powerful approach to shed light on disease mechanisms or relationships between genotype and phenotype in studies run over several years and involving tens of thousands of participants.

Link: lipotype.com/population-health-studies

webinars
human, plasma/serum, clinical, biomarker, diet, skin, neuro, cvd, diabetes, obesity
43
Molecular Metabolism

Plasma triacylglycerols are biomarkers of β-cell function in mice and humans

Ana Rodríguez Sánchez-Archidona, Céline Cruciani-Guglielmacci, Clara Roujeau, Leonore Wigger, Justine Lallement, Jessica Denom, Marko Barovic, Nadim Kassis, Florence Mehl, Jürgen Weitz, Marius Distler, Christian Klose, Kai Simons, Mark Ibberson, Michele Solimena, Christophe Magnan, Bernard Thorens

We conducted a systems biology approach to characterize the plasma lipidomes of C57Bl/6J, DBA/2J, and BALB/cJ mice under different nutritional conditions, as well as their pancreatic islet and liver transcriptomes. We searched for correlations between plasma lipids and tissue gene expression modules to find plasma biomarkers prognostic of type 2 diabetes, which could also inform on pancreatic β-cell deregulations or defects in the function of insulin target tissues. We identified strong correlation between plasma triacylglycerols (TAGs) and islet gene modules that comprise key regulators of glucose- and lipid-regulated insulin secretion and of the insulin signaling pathway, the two top hits were Gck and Abhd6 for negative and positive correlations, respectively. Correlations were also found between sphingomyelins and islet gene modules that overlapped in part with the gene modules correlated with TAGs. In the liver, the gene module most strongly correlated with plasma TAGs was enriched in mRNAs encoding fatty acid and carnitine transporters as well as multiple enzymes of the β-oxidation pathway. In humans, plasma TAGs also correlated with the expression of several of the same key regulators of insulin secretion and the insulin signaling pathway identified in mice. This cross-species comparative analysis further led to the identification of PITPNC1 as a candidate regulator of glucose-stimulated insulin secretion. TAGs emerge as biomarkers of a liver-to-β-cell axis that links hepatic β-oxidation to β-cell functional mass and insulin secretion.

Link: doi.org/10.1016/j.molmet.2021.101355

publications
mouse, plasma/serum, biomarker, diabetes
44
Developmental Cell

Cell cycle regulation of ER membrane biogenesis protects against chromosome missegregation

Holly Merta, Jake W Carrasquillo Rodríguez, Maya I Anjur-Dietrich, Tevis Vitale, Mitchell E Granade, Thurl E Harris, Daniel J Needleman, Shirin Bahmanyar

Failure to reorganize the endoplasmic reticulum (ER) in mitosis results in chromosome missegregation. Here, we show that accurate chromosome segregation in human cells requires cell cycle-regulated ER membrane production. Excess ER membranes increase the viscosity of the mitotic cytoplasm to physically restrict chromosome movements, which impedes the correction of mitotic errors leading to the formation of micronuclei. Mechanistically, we demonstrate that the protein phosphatase CTDNEP1 counteracts mTOR kinase to establish a dephosphorylated pool of the phosphatidic acid phosphatase lipin 1 in interphase. CTDNEP1 control of lipin 1 limits the synthesis of fatty acids for ER membrane biogenesis in interphase that then protects against chromosome missegregation in mitosis. Thus, regulation of ER size can dictate the biophysical properties of mitotic cells, providing an explanation for why ER reorganization is necessary for mitotic fidelity. Our data further suggest that dysregulated lipid metabolism is a potential source of aneuploidy in cancer cells.

Link: doi.org/10.1016/j.devcel.2021.11.009

publications
human, cells, basic science
45
Article

Cancer, Hypoxia & Mitochondria Lipids

Henri Deda, Nuala Del Piccolo

Though cancer is a heterogeneous disease, tumor microenvironments across organs share characteristic features. One of these features is hypoxia, or low oxygen tension. Hypoxia is considered a therapeutic target, but the molecular mechanisms underlying the role of hypoxia in cancer development and progression have not been fully described. A CRISPR-Cas9 knockout library in hepatocellular carcinoma cells was used to follow a hypoxia-driven negative selection process revealing that the protein “protein-tyrosine phosphatase mitochondrial 1” (PTPMT1) enables cells to adapt to hypoxic conditions.

Link: lipotype.com/mitochondrial-lipid-metabolism-in-hypoxic-cancer

articles
human, organ/tissue, mouse, cells, cancer
46
BBA MOLECULAR AND CELL BIOLOGY OF LIPIDS

Lipid droplets in skeletal muscle during grass snake (Natrix natrix L.) development

Magda Dubińska-Magiera, Damian Lewandowski, Dominik Cysewski, Seweryn Pawlak, Bartłomiej Najbar, Małgorzata Daczewska

Lipid droplets (LDs) are common organelles observed in Eucaryota. They are multifunctional organelles (involved in lipid storage, metabolism, and trafficking) that originate from endoplasmic reticulum (ER). LDs consist of a neutral lipid core, made up of diacyl- and triacylglycerols (DAGs and TAGs) and cholesterol esters (CEs), surrounded by a phospholipid monolayer and proteins, which are necessary for their structure and dynamics.

Here, we report the protein and lipid composition as well as characterization and dynamics of grass snake (Natrix natrix) skeletal muscle LDs at different developmental stages. In the present study, we used detailed morphometric, LC-MS, quantitative lipidomic analyses of LDs isolated from the skeletal muscles of the snake embryos, immunofluorescence, and TEM.

Our study also provides a valuable insight concerning the LDs’ multifunctionality and ability to interact with a variety of organelles. These LD features are reflected in their proteome composition, which contains scaffold proteins, metabolic enzymes signalling polypeptides, proteins necessary for the formation of docking sites, and many others. We also provide insights into the biogenesis and growth of muscle LDs goes beyond the conventional mechanism based on the synthesis and incorporation of TAGs and LD fusion. We assume that the formation and functioning of grass snake muscle LDs are based on additional mechanisms that have not yet been identified, which could be related to the unique features of reptiles that are manifested in the after-hatching period of life, such as a reptile-specific strategy for energy saving during hibernation.

Link: doi.org/10.1016/j.bbalip.2021.159086

publications
organelle, reptiles, basic science
47
iScience

Depletion of cardiac cardiolipin synthase alters systolic and diastolic function

Elia Smeir, Sarah Leberer, Annelie Blumrich, Georg Vogler, Anastasia Vasiliades, Sandra Dresen, Carsten Jaeger, Yoann Gloaguen, Christian Klose, Dieter Beule, P Christian Schulze, Rolf Bodmer, Anna Foryst-Ludwig, Ulrich Kintscher

Cardiolipin (CL) is a major cardiac mitochondrial phospholipid maintaining regular mitochondrial morphology and function in cardiomyocytes. Cardiac CL production includes its biosynthesis and a CL remodeling process. Here we studied the impact of CL biosynthesis and the enzyme cardiolipin synthase (CLS) on cardiac function. CLS and cardiac CL species were significantly downregulated in cardiomyocytes following catecholamine-induced cardiac damage in mice, accompanied by increased oxygen consumption rates, signs of oxidative stress, and mitochondrial uncoupling. RNAi-mediated cardiomyocyte-specific knockdown of CLS in Drosophila melanogaster resulted in marked cardiac dilatation, severe impairment of systolic performance, and slower diastolic filling velocity assessed by fluorescence-based heart imaging. Finally, we showed that CL72:8 is significantly decreased in cardiac samples from patients with heart failure with reduced ejection fraction (HFrEF). In summary, we identified CLS as a regulator of cardiac function. Considering the cardiac depletion of CL species in HFrEF, pharmacological targeting of CLS may be a promising therapeutic approach.

Link: doi.org/10.1016/j.isci.2021.103314

publications
human, organ/tissue, mouse, cells, cvd
48
Cell Reports

Regulatory T cell differentiation is controlled by αKG-induced alterations in mitochondrial metabolism and lipid homeostasis

Maria I Matias, Carmen S Yong, Amir Foroushani, Chloe Goldsmith, Cédric Mongellaz, Erdinc Sezgin, Kandice R Levental, Ali Talebi, Julie Perrault, Anais Rivière, Jonas Dehairs, Océane Delos, Justine Bertand-Michel, Jean-Charles Portais, Madeline Wong, Julien C Marie, Ameeta Kelekar, Sandrina Kinet, Valérie S Zimmermann, Ilya Levental, Laurent Yvan-Charvet, Johannes V Swinnen, Stefan A Muljo, Hector Hernandez-Vargas, Saverio Tardito, Naomi Taylor, Valérie Dardalhon

Suppressive regulatory T cell (Treg) differentiation is controlled by diverse immunometabolic signaling pathways and intracellular metabolites. Here we show that cell-permeable α-ketoglutarate (αKG) alters the DNA methylation profile of naive CD4 T cells activated under Treg polarizing conditions, markedly attenuating FoxP3+ Treg differentiation and increasing inflammatory cytokines. Adoptive transfer of these T cells into tumor-bearing mice results in enhanced tumor infiltration, decreased FoxP3 expression, and delayed tumor growth. Mechanistically, αKG leads to an energetic state that is reprogrammed toward a mitochondrial metabolism, with increased oxidative phosphorylation and expression of mitochondrial complex enzymes. Furthermore, carbons from ectopic αKG are directly utilized in the generation of fatty acids, associated with lipidome remodeling and increased triacylglyceride stores. Notably, inhibition of either mitochondrial complex II or DGAT2-mediated triacylglyceride synthesis restores Treg differentiation and decreases the αKG-induced inflammatory phenotype. Thus, we identify a crosstalk between αKG, mitochondrial metabolism and triacylglyceride synthesis that controls Treg fate.

Link: doi.org/10.1016/j.celrep.2021.109911

publications
human, inflammation, mouse, cells, immuno
49
Cell Reports

Proteomic and lipidomic profiling of demyelinating lesions identifies fatty acids as modulators in lesion recovery

Horst Penkert, Alix Bertrand, Vini Tiwari, Stephan Breimann, Stephan A Müller, Paul M Jordan, Mathias J Gerl, Christian Klose, Ludovico Cantuti-Castelvetri, Mar Bosch-Queralt, Ilya Levental, Stefan F Lichtenthaler, Oliver Werz, Mikael Simons

After demyelinating injury of the central nervous system, resolution of the mounting acute inflammation is crucial for the initiation of a regenerative response. Here, we aim to identify fatty acids and lipid mediators that govern the balance of inflammatory reactions within demyelinating lesions. Using lipidomics, we identify bioactive lipids in the resolution phase of inflammation with markedly elevated levels of n-3 polyunsaturated fatty acids. Using fat-1 transgenic mice, which convert n-6 fatty acids to n-3 fatty acids, we find that reduction of the n-6/n-3 ratio decreases the phagocytic infiltrate. In addition, we observe accelerated decline of microglia/macrophages and enhanced generation of oligodendrocytes in aged mice when n-3 fatty acids are shuttled to the brain. Thus, n-3 fatty acids enhance lesion recovery and may, therefore, provide the basis for pro-regenerative medicines of demyelinating diseases in the central nervous system.

Link: doi.org/10.1016/j.celrep.2021.109898

publications
organ/tissue, inflammation, mouse, neuro, immuno
50
PNAS

Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency

Marija Dulovic-Mahlow, Frida Mandik, Lisa Frese, Yuliia Kanana, Sokhna H Diaw, Julia Depperschmidt, Claudia Böhm, Jonas Rohr, Thora Lohnau, Inke R König, Christine Klein

Energy production via the mitochondrial electron transport chain (ETC) and mitophagy are two important processes affected in Parkinson’s disease (PD). Interestingly, PINK1, mutations of which cause early-onset PD, plays a key role in both processes, suggesting that these two mechanisms are connected. However, the converging link of both pathways currently remains enigmatic. Recent findings demonstrated that lipid aggregation, along with defective mitochondria, is present in postmortem brains of PD patients. In addition, an increasing body of evidence shows that sphingolipids, including ceramide, are altered in PD, supporting the importance of lipids in the pathophysiology of PD. Here, we identified ceramide to play a crucial role in PINK1-related PD that was previously linked almost exclusively to mitochondrial dysfunction. We found ceramide to accumulate in mitochondria and to negatively affect mitochondrial function, most notably the ETC. Lowering ceramide levels improved mitochondrial phenotypes in pink1-mutant flies and PINK1-deficient patient-derived fibroblasts, showing that the effects of ceramide are evolutionarily conserved. In addition, ceramide accumulation provoked ceramide-induced mitophagy upon PINK1 deficiency. As a result of the ceramide accumulation, β-oxidation in PINK1 mutants was decreased, which was rescued by lowering ceramide levels. Furthermore, stimulation of β-oxidation was sufficient to rescue PINK1-deficient phenotypes. In conclusion, we discovered a cellular mechanism resulting from PD-causing loss of PINK1 and found a protective role of β-oxidation in ETC dysfunction, thus linking lipids and mitochondria in the pathophysiology of PINK1-related PD. Furthermore, our data nominate β-oxidation and ceramide as therapeutic targets for PD.

Link: doi.org/10.1073/pnas.2025347118

publications
organ/tissue, organelle, insects, neuro
51
The Lipidomics Webinar

Are Mouse & Lipidomics the Perfect Match?

Christian Klose

Lipidomics is an indispensable method for the quantitative assessment of lipid metabolism in basic, clinical, and pharmaceutical research. It allows for the generation of information-dense datasets in a large variety of experimental setups and model organisms and is successfully applied in translation research.
Previous research, mostly conducted in mice (Mus musculus), has shown a remarkable specificity of the lipid compositions of different cell types, tissues, and organs. However, a systematic analysis of the overall complexity and variation of the mouse lipidome is lacking. Thus, we have investigated lipid compositions of different mouse organs and tissues and the effects of diet, sex, and genotype on the mouse lipidomes.
We provide insights into the organ-specific lipidomic variation. This analyses serve as a valuable resource for experimental design (for example for sample number estimation) and facilitate interpretation of lipidomic phenotypes in mouse studies, including time-dose or mode-of-action studies in pharmaceutical research.

Link: lipotype.com/mouse-lipidomics-for-clinical-research

webinars
organ/tissue, mouse, blood, plasma/serum, clinical, biomarker, diet, pharma, method
52
International Journal of Molecular Sciences

Histone Deacetylase Inhibition Regulates Lipid Homeostasis in a Mouse Model of Amyotrophic Lateral Sclerosis

Thibaut Burg, Elisabeth Rossaert, Matthieu Moisse, Philip Van Damme, Ludo Van Den Bosch

Amyotrophic lateral sclerosis (ALS) is an incurable and fatal neurodegenerative disorder of the motor system. While the etiology is still incompletely understood, defects in metabolism act as a major contributor to the disease progression. Recently, histone deacetylase (HDAC) inhibition using ACY-738 has been shown to restore metabolic alterations in the spinal cord of a FUS mouse model of ALS, which was accompanied by a beneficial effect on the motor phenotype and survival. In this study, we investigated the specific effects of HDAC inhibition on lipid metabolism using untargeted lipidomic analysis combined with transcriptomic analysis in the spinal cord of FUS mice. We discovered that symptomatic FUS mice recapitulate lipid alterations found in ALS patients and in the SOD1 mouse model. Glycerophospholipids, sphingolipids, and cholesterol esters were most affected. Strikingly, HDAC inhibition mitigated lipid homeostasis defects by selectively targeting glycerophospholipid metabolism and reducing cholesteryl esters accumulation. Therefore, our data suggest that HDAC inhibition is a potential new therapeutic strategy to modulate lipid metabolism defects in ALS and potentially other neurodegenerative diseases.

Link: doi.org/10.3390/ijms222011224

publications
organ/tissue, mouse, pharma, neuro
53
ARTICLE

Multiomics Profiling of Alzheimer’s Disease

Henri Deda, Nuala Del Piccolo

The human nervous system generates motion, regulates bodily functions, and transmits information about environmental conditions. These functions are essential to life; hence the nervous system has several layers of protection. Despite its natural defenses, the nervous system is susceptible to multiple degenerative diseases. Alzheimer’s disease involves progressive neurodegeneration – or, damage to neurons and loss of communication between neurons. Multiomics technologies identify and quantity molecules in tissue samples. Through comparison of multiomics analyses across samples, molecular signaling pathways involved in physiological and pathological processes that explain variance and predict disease progression were identified.

Link: lipotype.com/multiomics-analysis-and-alzheimers-disease

articles
human, aging, clinical, biomarker, csf, neuro
54
MDPI Cells

Mitochondrial Phospholipid Homeostasis Is Regulated by the i-AAA Protease PaIAP and Affects Organismic Aging

Timo Löser, Aljoscha Joppe, Andrea Hamann, Heinz D Osiewacz

Mitochondria are ubiquitous organelles of eukaryotic organisms with a number of essential functions, including synthesis of iron-sulfur clusters, amino acids, lipids, and adenosine triphosphate (ATP). During aging of the fungal aging model Podospora anserina, the inner mitochondrial membrane (IMM) undergoes prominent morphological alterations, ultimately resulting in functional impairments. Since phospholipids (PLs) are key components of biological membranes, maintenance of membrane plasticity and integrity via regulation of PL biosynthesis is indispensable. Here, we report results from a lipidomic analysis of isolated mitochondria from P. anserina that revealed an age-related reorganization of the mitochondrial PL profile and the involvement of the i-AAA protease PaIAP in proteolytic regulation of PL metabolism. The absence of PaIAP enhances biosynthesis of characteristic mitochondrial PLs, leads to significant alterations in the acyl composition of the mitochondrial signature PL cardiolipin (CL), and induces mitophagy. These alterations presumably cause the lifespan increase of the PaIap deletion mutant under standard growth conditions. However, PaIAP is required at elevated temperatures and for degradation of superfluous CL synthase PaCRD1 during glycolytic growth. Overall, our study uncovers a prominent role of PaIAP in the regulation of PL homeostasis in order to adapt membrane plasticity to fluctuating environmental conditions as they occur in nature.

Link: doi.org/10.3390/cells10102775

publications
organelle, other fungi, basic science
55
Journal of Obesity

Proteomic and Metabolomic Characterization of Metabolically Healthy Obesity: A Descriptive Study from a Swedish Cohort

Johan Korduner, Peter M Nilsson, Olle Melander, Mathias J Gerl, Gunnar Engström, Erasmus Bachus, Martin Magnusson, Filip Ottosson

Obesity is a well-established risk factor for the development of numerous chronic diseases. However, there is a small proportion of obese individuals that seem to escape these aforementioned conditions—Metabolically Healthy Obesity (MHO). Our aim was to do a metabolic and biomarker profiling of MHO individuals. Associations between different biomarkers (proteomics, lipidomics, and metabolomics) coupled to either MHO or metabolically unhealthy obese (MUO) individuals were analyzed through principal component analysis (PCA). Subjects were identified from a subsample of 416 obese individuals, selected from the Malmö Diet and Cancer study—Cardiovascular arm (MDCS-CV, n = 3,443). They were further divided into MHO (n = 143) and MUO (n = 273) defined by a history of hospitalization, or not, at baseline inclusion, and nonobese subjects (NOC, n = 3,027). Two distinctive principle components (PL2, PP5) were discovered with a significant difference and thus further investigated through their main loadings. MHO individuals had a more metabolically favorable lipid and glucose profile than MUO subjects, that is, lower levels of traditional blood glucose and triglycerides, as well as a trend of lower metabolically unfavorable lipid biomarkers. PL2 (lipidomics, p = 0.02) showed stronger associations of triacylglycerides with MUO, whereas phospholipids correlated with MHO. PP5 (proteomics, p = 0.01) included interleukin-1 receptor antagonist (IL-1ra) and leptin with positive relations to MUO and galanin that correlated positively to MHO. The group differences in metabolite profiles were to a large extent explained by factors included in the metabolic syndrome. Compared to MUO individuals, corresponding MHO individuals present with a more favorable lipid metabolic profile, accompanied by a downregulation of potentially harmful proteomic biomarkers. This unique and extensive biomarker profiling presents novel data on potentially differentiating traits between these two obese phenotypes.

Link: doi.org/10.1155/2021/6616983

publications
human, plasma/serum, clinical, biomarker, obesity
56
Journal of Experimental Medicine

TREM2-dependent lipid droplet biogenesis in phagocytes is required for remyelination

Garyfallia Gouna, Christian Klose, Mar Bosch-Queralt, Lu Liu, Ozgun Gokce, Martina Schifferer, Ludovico Cantuti-Castelvetri, Mikael Simons

Upon demyelinating injury, microglia orchestrate a regenerative response that promotes myelin repair, thereby restoring rapid signal propagation and protecting axons from further damage. Whereas the essential phagocytic function of microglia for remyelination is well known, the underlying metabolic pathways required for myelin debris clearance are poorly understood. Here, we show that cholesterol esterification in male mouse microglia/macrophages is a necessary adaptive response to myelin debris uptake and required for the generation of lipid droplets upon demyelinating injury. When lipid droplet biogenesis is defective, innate immune cells do not resolve, and the regenerative response fails. We found that triggering receptor expressed on myeloid cells 2 (TREM2)–deficient mice are unable to adapt to excess cholesterol exposure, form fewer lipid droplets, and build up endoplasmic reticulum (ER) stress. Alleviating ER stress in TREM2-deficient mice restores lipid droplet biogenesis and resolves the innate immune response. Thus, we conclude that TREM2-dependent formation of lipid droplets constitute a protective response required for remyelination to occur.

Link: doi.org/10.1084/jem.20210227

publications
mouse, cells, neuro
57
MDPI Molecular Sciences

Lipidomic and Proteomic Alterations Induced by Even and Odd Medium-Chain Fatty Acids on Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders

Khaled I Alatibi, Stefan Tholen, Zeinab Wehbe, Judith Hagenbuchner, Daniela Karall, Michael J Ausserlechner, Oliver Schilling, Sarah C Grünert, Jerry Vockley, Sara Tucci

Medium-chain fatty acids (mc-FAs) are currently applied in the treatment of long-chain fatty acid oxidation disorders (lc-FAOD) characterized by impaired β-oxidation. Here, we performed lipidomic and proteomic analysis in fibroblasts from patients with very long-chain acyl-CoA dehydrogenase (VLCADD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) deficiencies after incubation with heptanoate (C7) and octanoate (C8). Defects of β-oxidation induced striking proteomic alterations, whereas the effect of treatment with mc-FAs was minor. However, mc-FAs induced a remodeling of complex lipids. Especially C7 appeared to act protectively by restoring sphingolipid biosynthesis flux and improving the observed dysregulation of protein homeostasis in LCHADD under control conditions.

Link: doi.org/10.3390/ijms221910556

publications
human, inflammation, cells, diet
58
Scientific Reports

Mouse lipidomics reveals inherent flexibility of a mammalian lipidome

Michal A Surma, Mathias J Gerl, Ronny Herzog, Jussi Helppi, Kai Simons, Christian Klose

Lipidomics has become an indispensable method for the quantitative assessment of lipid metabolism in basic, clinical, and pharmaceutical research. It allows for the generation of information-dense datasets in a large variety of experimental setups and model organisms. Previous studies, mostly conducted in mice (Mus musculus), have shown a remarkable specificity of the lipid compositions of different cell types, tissues, and organs. However, a systematic analysis of the overall variation of the mouse lipidome is lacking. To fill this gap, in the present study, the effect of diet, sex, and genotype on the lipidomes of mouse tissues, organs, and bodily fluids has been investigated. Baseline quantitative lipidomes consisting of 796 individual lipid molecules belonging to 24 lipid classes are provided for 10 different sample types. Furthermore, the susceptibility of lipidomes to the tested parameters is assessed, providing insights into the organ-specific lipidomic plasticity and flexibility. This dataset provides a valuable resource for basic and pharmaceutical researchers working with murine models and complements existing proteomic and transcriptomic datasets. It will inform experimental design and facilitate interpretation of lipidomic datasets.

Link: doi.org/10.1038/s41598-021-98702-5

publications
organ/tissue, mouse, blood, plasma/serum, clinical, biomarker, diet, pharma, method
59
Article

Clinical Indicators of Metabolic Obesity

Henri Deda, Nuala Del Piccolo

Obesity is linked to a number of health problems – including cardiovascular disease and type II diabetes – and afflicts over 650 million adults worldwide (~13% of the population). The incidence of obesity is rising so rapidly that many scientists and healthcare workers consider obesity to be a pandemic. To diagnose obesity, clinicians and researchers estimate body fat using a series of indicators. Unfortunately, these standard indicators struggle to accurately classify individuals by obesity status. They do not account for known heterogeneity in body fat with age, sex, and ethnicity. Recent research suggests that molecular measures of metabolism – for example, of cholesterol or metabolomics in the plasma – may classify obesity status more accurately than standard indicators. Additionally, lipid profiles in the body may detect, predict, and/or stratify patients with other diseases. In this study, shotgun mass spectrometry was used to characterize the plasma lipidome of 1,061 samples from the 2012 National FINRISK Study. Next, these data were used to train a series of machine learning models to estimate indicators of obesity. Then, the best-fit machine learning model was validated on a second plasma lipidome dataset, which was composed of 250 samples from the 2014 Malmö Diet and Cancer Cardiovascular Cohort. The study results show that the plasma lipidome can reveal features of obesity inaccessible by existing indicators and the model may improve the identification of patients in need for weight reducing therapy who do not qualify by BMI.

Link: lipotype.com/clinical-indicators-of-metabolic-obesity

articles
clinical, biomarker, obesity
60
The Lipidomics Webinar

Lipids are Cool Again!

Kai Simons

Before the DNA revolution the lipids were center stage in cell membrane research and also important players in metabolic research. But then they slowly disappeared into the background, being relegated to a boring matrix for proteins in membranes. This is now changing.
Lipids are coming back on all fronts. They regulate the functions of cell membranes essential for life. The lipid composition in cells is tightly regulated to allow cell metabolism to function as a coordinated whole. This homeostasis is today under threat because our lifestyle is out of sync, causing an obesity pandemic with deadly consequences.
We developed a mass spectrometry-based platform with unprecedented precision and have used this technology to analyze and establish multi-parametric lipid signatures that measure health and disease. Our data suggest that the blood lipidome reflects the metabolic status of the body. These lipidomic profiles could provide a navigation tool to stem the obesity affliction.

Link: lipotype.com/introduction-to-lipids-and-lipidomics

webinars
human, plasma/serum, clinical, biomarker, diet, obesity
61
The EMBO Journal

Shortening of membrane lipid acyl chains compensates for phosphatidylcholine deficiency in choline-auxotroph yeast

Xue Bao, Martijn C Koorengevel, Marian J A Groot Koerkamp, Amir Homavar, Amrah Weijn, Stefan Crielaard, Mike F Renne, Joseph H Lorent, Willie J C Geerts, Michal A Surma, Muriel Mari, Frank C P Holstege, Christian Klose, Anton I P M de Kroon

Phosphatidylcholine (PC) is an abundant membrane lipid component in most eukaryotes, including yeast, and has been assigned multiple functions in addition to acting as building block of the lipid bilayer. Here, by isolating S. cerevisiae suppressor mutants that exhibit robust growth in the absence of PC, we show that PC essentiality is subject to cellular evolvability in yeast. The requirement for PC is suppressed by monosomy of chromosome XV or by a point mutation in the ACC1 gene encoding acetyl-CoA carboxylase. Although these two genetic adaptations rewire lipid biosynthesis in different ways, both decrease Acc1 activity, thereby reducing average acyl chain length. Consistently, soraphen A, a specific inhibitor of Acc1, rescues a yeast mutant with deficient PC synthesis. In the aneuploid suppressor, feedback inhibition of Acc1 through acyl-CoA produced by fatty acid synthase (FAS) results from upregulation of lipid synthesis. The results show that budding yeast regulates acyl chain length by fine-tuning the activities of Acc1 and FAS and indicate that PC evolved by benefitting the maintenance of membrane fluidity.

Link: doi.org/10.15252/embj.2021107966

publications
cells, yeast, basic science
62
Metabolites

Cross-Platform Evaluation of Commercially Targeted and Untargeted Metabolomics Approaches to Optimize the Investigation of Psychiatric Disease

Lauren E Chaby, Heather C Lasseter, Kévin Contrepois, Reza M Salek, Christoph W Turck, Andrew Thompson, Timothy Vaughan, Magali Haas, Andreas Jeromin

Metabolomics methods often encounter trade-offs between quantification accuracy and coverage, with truly comprehensive coverage only attainable through a multitude of complementary assays. Due to the lack of standardization and the variety of metabolomics assays, it is difficult to integrate datasets across studies or assays. To inform metabolomics platform selection, with a focus on posttraumatic stress disorder (PTSD), we review platform use and sample sizes in psychiatric metabolomics studies and then evaluate five prominent metabolomics platforms for coverage and performance, including intra-/inter-assay precision, accuracy, and linearity. We found performance was variable between metabolite classes, but comparable across targeted and untargeted approaches. Within all platforms, precision and accuracy were highly variable across classes, ranging from 0.9–63.2% (coefficient of variation) and 0.6–99.1% for accuracy to reference plasma. Several classes had high inter-assay variance, potentially impeding dissociation of a biological signal, including glycerophospholipids, organooxygen compounds, and fatty acids. Coverage was platform-specific and ranged from 16–70% of PTSD-associated metabolites. Non-overlapping coverage is challenging; however, benefits of applying multiple metabolomics technologies must be weighed against cost, biospecimen availability, platform-specific normative levels, and challenges in merging datasets. Our findings and open-access cross-platform dataset can inform platform selection and dataset integration based on platform-specific coverage breadth/overlap and metabolite-specific performance.

Link: doi.org/10.3390/metabo11090609

publications
human, plasma/serum, clinical, biomarker, neuro, method
63
Article

Variability of Skin Lipidomics Profiles

Henri Deda, Nuala Del Piccolo

Human skin is a dynamic organ that functions as a protective barrier between an individual and their environment. The uppermost layer of the skin, the stratum corneum, is composed of sheets of keratinocytes embedded in a lipid-rich extracellular matrix. The skin lipid profile is known to vary with factors like age, sex, season of the year, and certain skin conditions. These relationships have not been comprehensively characterized, but may affect skin barrier function. To address this gap, the lipid profile in skin samples from 104 individuals was characterized using mass spectrometry-based lipidomics. The results reveal how the skin lipidome varies with skin depth, within individuals, and between individuals.

Link: lipotype.com/skin-lipid-profile-analysis-and-variability

articles
human, skin, cosmetics
64
MDPI Microorganisms

The Role of Sch9 and the V-ATPase in the Adaptation Response to Acetic Acid and the Consequences for Growth and Chronological Lifespan

Marie-Anne Deprez, Jeroen M Maertens, Lisbeth Olsson, Maurizio Bettiga, Joris Winderickx

Studies with Saccharomyces cerevisiae indicated that non-physiologically high levels of acetic acid promote cellular acidification, chronological aging, and programmed cell death. In the current study, we compared the cellular lipid composition, acetic acid uptake, intracellular pH, growth, and chronological lifespan of wild-type cells and mutants lacking the protein kinase Sch9 and/or a functional V-ATPase when grown in medium supplemented with different acetic acid concentrations. Our data show that strains lacking the V-ATPase are especially more susceptible to growth arrest in the presence of high acetic acid concentrations, which is due to a slower adaptation to the acid stress. These V-ATPase mutants also displayed changes in lipid homeostasis, including alterations in their membrane lipid composition that influences the acetic acid diffusion rate and changes in sphingolipid metabolism and the sphingolipid rheostat, which is known to regulate stress tolerance and longevity of yeast cells. However, we provide evidence that the supplementation of 20 mM acetic acid has a cytoprotective and presumable hormesis effect that extends the longevity of all strains tested, including the V-ATPase compromised mutants. We also demonstrate that the long-lived sch9Δ strain itself secretes significant amounts of acetic acid during stationary phase, which in addition to its enhanced accumulation of storage lipids may underlie its increased lifespan.

Link: doi.org/10.3390/microorganisms9091871

publications
aging, cells, yeast
65
Scientific Reports

Molecular-dynamics-simulation-guided membrane engineering allows the increase of membrane fatty acid chain length in Saccharomyces cerevisiae

Jeroen M Maertens, Simone Scrima, Matteo Lambrughi, Samuel Genheden, Cecilia Trivellin, Leif A Eriksson, Elena Papaleo, Lisbeth Olsson, Maurizio Bettiga

The use of lignocellulosic-based fermentation media will be a necessary part of the transition to a circular bio-economy. These media contain many inhibitors to microbial growth, including acetic acid. Under industrially relevant conditions, acetic acid enters the cell predominantly through passive diffusion across the plasma membrane. The lipid composition of the membrane determines the rate of uptake of acetic acid, and thicker, more rigid membranes impede passive diffusion. We hypothesized that the elongation of glycerophospholipid fatty acids would lead to thicker and more rigid membranes, reducing the influx of acetic acid. Molecular dynamics simulations were used to predict the changes in membrane properties. Heterologous expression of Arabidopsis thaliana genes fatty acid elongase 1 (FAE1) and glycerol-3-phosphate acyltransferase 5 (GPAT5) increased the average fatty acid chain length. However, this did not lead to a reduction in the net uptake rate of acetic acid. Despite successful strain engineering, the net uptake rate of acetic acid did not decrease. We suggest that changes in the relative abundance of certain membrane lipid headgroups could mitigate the effect of longer fatty acid chains, resulting in a higher net uptake rate of acetic acid.

Link: doi.org/10.1038/s41598-021-96757-y

publications
cells, yeast, basic science
66
Environmental Epimediology

Assessing the impact of exposome on the course of chronic obstructive pulmonary disease and cystic fibrosis

Manon Benjdir, Étienne Audureau, Ariel Beresniak, Patrice Coll, Ralph Epaud, Kristina Fiedler, Bénédicte Jacquemin, Laurent Niddam, Spyros N Pandis, Gerhard Pohlmann, Torkjel M Sandanger, Kai Simons, Mette Sørensen, Patrick Wagner, Sophie Lanone

Because of the direct interaction of lungs with the environment, respiratory diseases are among the leading causes of environment-related deaths in the world. Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are two highly debilitating diseases that are of particular interest in the context of environmental studies; they both are characterized by a similar progressive loss of lung function with small bronchi alterations, and a high phenotypic variability of unknown origin, which prevents a good therapeutic efficacy. In the last years, there has been an evolution in the apprehension of the study of diseases going from a restricted “one exposure, one disease” approach to a broader concept with other associating factors, the exposome. The overall objective of the REMEDIA project is to extend the understanding of the contribution of the exposome to COPD and CF diseases. To achieve our aim, we will (1) exploit data from existing cohorts and population registries to create a unified global database gathering phenotype and exposome information; (2) develop a flexible individual sensor device combining environmental and biomarker toolkits; (3) use a versatile atmospheric simulation chamber to simulate the health effects of complex exposomes; (4) use machine learning supervised analyses and causal inference models to identify relevant risk factors; and (5) develop econometric and cost-effectiveness models to assess the costs, performance, and cost-effectiveness of a selection of prevention strategies. The results will be used to develop guidelines to better predict disease risks and constitute the elements of the REMEDIA toolbox. The multidisciplinary approach carried out by the REMEDIA European project should represent a major breakthrough in reducing the morbidity and mortality associated with COPD and CF diseases.

Link: doi.org/10.1097/EE9.0000000000000165

publications
human, clinical, biomarker
67
The EMBO Journal

Torsin and NEP1R1-CTDNEP1 phosphatase affect interphase nuclear pore complex insertion by lipid-dependent and lipid-independent mechanisms

Julie Jacquemyn, Joyce Foroozandeh, Katlijn Vints, Jef Swerts, Patrik Verstreken, Natalia V Gounko, Sandra F Gallego, Rose E Goodchild

The interphase nuclear envelope (NE) is extensively remodeled during nuclear pore complex (NPC) insertion. How this remodeling occurs and why it requires Torsin ATPases, which also regulate lipid metabolism, remains poorly understood. Here, we show that Drosophila Torsin (dTorsin) affects lipid metabolism via the NEP1R1-CTDNEP1 phosphatase and the Lipin phosphatidic acid (PA) phosphatase. This includes that Torsins remove NEP1R1-CTDNEP1 from the NE in fly and mouse cells, leading to subsequent Lipin exclusion from the nucleus. NEP1R1-CTDNEP1 downregulation also restores nuclear pore membrane fusion in post-mitotic dTorsinKO fat body cells. However, dTorsin-associated nuclear pore defects do not correlate with lipidomic abnormalities and are not resolved by silencing of Lipin. Further testing confirmed that membrane fusion continues in cells with hyperactivated Lipin. It also led to the surprising finding that excessive PA metabolism inhibits recruitment of the inner ring complex Nup35 subunit, resulting in elongated channel-like structures in place of mature nuclear pores. We conclude that the NEP1R1-CTDNEP1 phosphatase affects interphase NPC biogenesis by lipid-dependent and lipid-independent mechanisms, explaining some of the pleiotropic effects of Torsins.

Link: doi.org/10.15252/embj.2020106914

publications
organ/tissue, insects, basic science
68
Article

Cardiac Lipid Metabolism in Heart Failure

Henri Deda, Nuala Del Piccolo

Heart failure occurs when the organ progressively loses its capacity to pump blood to the rest of the body. The condition is typically caused by damage to cardiac tissue through myocardial infarction, coronary artery disease, or genetics. Heart failure is accompanied by an increase in lipid metabolism in adipose tissue, cardiac tissue, and other organs. As a result, the lipidome – which is hypothesized to modulate heart function – is altered. Moreover, a growing body of evidence suggests a key role for cross-tissue/organ communication in physiology and pathology. Hence, lipidomic analyses during heart failure may elucidate the mechanisms of disease, identify novel therapeutic targets, and represent a non-invasive diagnostic tool. Here, lipid metabolism during left-sided systolic heart failure was investigated in mice and humans. The results suggest that lipid metabolism in adipose tissue may regulate cardiac tissue function.

Link: lipotype.com/cardiac-lipid-metabolism-after-heart-failure

articles
human, organ/tissue, mouse, plasma/serum, biomarker, cvd
69
EBioMedicine

Shotgun mass spectrometry-based lipid profiling identifies and distinguishes between chronic inflammatory diseases

Rune Matthiesen, Chris Lauber, Júlio L Sampaio, Neuza Domingues, Liliana Alves, Mathias J Gerl, Manuel S Almeida, Gustavo Rodrigues, Pedro Araújo-Gonçalves, Jorge Ferreira, Claudia Borbinha, João Pedro Marto, Marisa Neves, Frederico Batista, Miguel Viana-Baptista, Jose Alves, Kai Simons, Winchil L C Vaz, Otilia V Vieira

Localized stress and cell death in chronic inflammatory diseases may release tissue-specific lipids into the circulation causing the blood plasma lipidome to reflect the type of inflammation. However, deep lipid profiles of major chronic inflammatory diseases have not been compared.
Plasma lipidomes of patients suffering from two etiologically distinct chronic inflammatory diseases, atherosclerosis-related vascular disease, including cardiovascular (CVD) and ischemic stroke (IS), and systemic lupus erythematosus (SLE), were screened by a top-down shotgun mass spectrometry-based analysis without liquid chromatographic separation and compared to each other and to age-matched controls. Lipid profiling of 596 lipids was performed on a cohort of 427 individuals. Machine learning classifiers based on the plasma lipidomes were used to distinguish the two chronic inflammatory diseases from each other and from the controls.
Analysis of the lipidomes enabled separation of the studied chronic inflammatory diseases from controls based on independent validation test set classification performance (CVD vs control – Sensitivity: 0.94, Specificity: 0.88; IS vs control – Sensitivity: 1.0, Specificity: 1.0; SLE vs control – Sensitivity: 1, Specificity: 0.93) and from each other (SLE vs CVD ‒ Sensitivity: 0.91, Specificity: 1; IS vs SLE – Sensitivity: 1, Specificity: 0.82). Preliminary linear discriminant analysis plots using all data clearly separated the clinical groups from each other and from the controls, and partially separated CVD severities, as classified into five clinical groups. Dysregulated lipids are partially but not fully counterbalanced by statin treatment.
Dysregulation of the plasma lipidome is characteristic of chronic inflammatory diseases. Lipid profiling accurately identifies the diseases and in the case of CVD also identifies sub-classes.

Link: doi.org/10.1016/j.ebiom.2021.103504

publications
human, inflammation, plasma/serum, clinical, biomarker, cvd, immuno
70
PLOS Genetics

Increased mitochondrial protein import and cardiolipin remodelling upon early mtUPR

Daniel Poveda-Huertes, Asli A Taskin, Ines Dhaouadi, Lisa Myketin, Adinarayana Marada, Lukas Habernig, Sabrina Büttner, F-Nora Vögtle

Mitochondrial defects can cause a variety of human diseases and protective mechanisms exist to maintain mitochondrial functionality. Imbalances in mitochondrial proteostasis trigger a transcriptional program, termed mitochondrial unfolded protein response (mtUPR). However, the temporal sequence of events in mtUPR is unclear and the consequences on mitochondrial protein import are controversial. Here, we have quantitatively analyzed all main import pathways into mitochondria after different time spans of mtUPR induction. Kinetic analyses reveal that protein import into all mitochondrial subcompartments strongly increases early upon mtUPR and that this is accompanied by rapid remodelling of the mitochondrial signature lipid cardiolipin. Genetic inactivation of cardiolipin synthesis precluded stimulation of protein import and compromised cellular fitness. At late stages of mtUPR upon sustained stress, mitochondrial protein import efficiency declined. Our work clarifies the enigma of protein import upon mtUPR and identifies sequential mtUPR stages, in which an early increase in protein biogenesis to restore mitochondrial proteostasis is followed by late stages characterized by a decrease in import capacity upon prolonged stress induction.

Link: doi.org/10.1371/journal.pgen.1009664

publications
organelle, yeast, basic science
71
Nature Metabolism

Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories towards type 2 diabetes

Leonore Wigger, Marko Barovic, Andreas-David Brunner, Flavia Marzetta, Eyke Schöniger, Florence Mehl, Nicole Kipke, Daniela Friedland, Frederic Burdet, Camille Kessler, Mathias Lesche, Bernard Thorens, Ezio Bonifacio, Cristina Legido-Quigley, Pierre Barbier Saint Hilaire, Philippe Delerive, Andreas Dahl, Christian Klose, Mathias J Gerl, Kai Simons, Daniela Aust, Jürgen Weitz, Marius Distler, Anke M Schulte, Matthias Mann, Mark Ibberson, Michele Solimena

Most research on human pancreatic islets is conducted on samples obtained from normoglycaemic or diseased brain-dead donors and thus cannot accurately describe the molecular changes of pancreatic islet beta cells as they progress towards a state of deficient insulin secretion in type 2 diabetes (T2D). Here, we conduct a comprehensive multi-omics analysis of pancreatic islets obtained from metabolically profiled pancreatectomized living human donors stratified along the glycemic continuum, from normoglycemia to T2D. We find that islet pools isolated from surgical samples by laser-capture microdissection display remarkably more heterogeneous transcriptomic and proteomic profiles in patients with diabetes than in non-diabetic controls. The differential regulation of islet gene expression is already observed in prediabetic individuals with impaired glucose tolerance. Our findings demonstrate a progressive, but disharmonic, remodelling of mature beta cells, challenging current hypotheses of linear trajectories toward precursor or transdifferentiation stages in T2D. Furthermore, through integration of islet transcriptomics with preoperative blood plasma lipidomics, we define the relative importance of gene coexpression modules and lipids that are positively or negatively associated with HbA1c levels, pointing to potential prognostic markers.

Link: doi.org/10.1038/s42255-021-00420-9

publications
human, plasma/serum, clinical, biomarker, diabetes
72
Article

Multiomics Analysis in Type 1 Diabetes Research

Henri Deda, Nuala Del Piccolo

Insulin, a hormone produced by beta cells in the pancreas, regulates sugar levels in the bloodstream and metabolic processes in the liver. Insulin deficiency occurs when beta cells stop producing insulin; this is the primary cause of type I diabetes. Insulin deficiency inhibits glucose and lipid storage and metabolism throughout the body, which can lead to fatigue, blindness, and even death. And insulin plays a key role in regulating metabolism of glucose, glycogen, and fatty acids in the liver. However, the impact of chronic insulin deficiency on liver function is incompletely characterized. To address this gap, the research team analyzed diabetic and wild-type liver tissue from their biobank using multiomics: namely, transcriptomics, proteomics, metabolomics, and lipidomics.

Link: lipotype.com/multiomics-in-type-1-diabetes-research

articles
organ/tissue, plasma/serum, clinical, other mammals, biomarker, diabetes
73
Diabetologia

Replication and cross-validation of type 2 diabetes subtypes based on clinical variables: an IMI-RHAPSODY study

Roderick C Slieker, Louise A Donnelly, Hugo Fitipaldi, Gerard A Bouland, Giuseppe N Giordano, Mikael Åkerlund, Mathias J Gerl, Emma Ahlqvist, Ashfaq Ali, Iulian Dragan, Andreas Festa, Michael K Hansen, Dina Mansour Aly, Min Kim, Dmitry Kuznetsov, Florence Mehl, Christian Klose, Kai Simons, Imre Pavo, Timothy J Pullen, Tommi Suvitaival, Asger Wretlind, Peter Rossing, Valeriya Lyssenko, Cristina Legido-Quigley, Leif Groop, Bernard Thorens, Paul W Franks, Mark Ibberson, Guy A Rutter, Joline W J Beulens, Leen M ‘t Hart, Ewan R Pearson

Five clusters based on clinical characteristics have been suggested as diabetes subtypes: one autoimmune and four subtypes of type 2 diabetes. In the current study we replicate and cross-validate these type 2 diabetes clusters in three large cohorts using variables readily measured in the clinic.
In three independent cohorts, in total 15,940 individuals were clustered based on age, BMI, HbA1c, random or fasting C-peptide, and HDL-cholesterol. Clusters were cross-validated against the original clusters based on HOMA measures. In addition, between cohorts, clusters were cross-validated by re-assigning people based on each cohort’s cluster centres. Finally, we compared the time to insulin requirement for each cluster.
Five distinct type 2 diabetes clusters were identified and mapped back to the original four All New Diabetics in Scania (ANDIS) clusters. Using C-peptide and HDL-cholesterol instead of HOMA2-B and HOMA2-IR, three of the clusters mapped with high sensitivity (80.6–90.7%) to the previously identified severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD) and mild obesity-related diabetes (MOD) clusters. The previously described ANDIS mild age-related diabetes (MARD) cluster could be mapped to the two milder groups in our study: one characterised by high HDL-cholesterol (mild diabetes with high HDL-cholesterol [MDH] cluster), and the other not having any extreme characteristic (mild diabetes [MD]). When these two milder groups were combined, they mapped well to the previously labelled MARD cluster (sensitivity 79.1%). In the cross-validation between cohorts, particularly the SIDD and MDH clusters cross-validated well, with sensitivities ranging from 73.3% to 97.1%. SIRD and MD showed a lower sensitivity, ranging from 36.1% to 92.3%, where individuals shifted from SIRD to MD and vice versa. People belonging to the SIDD cluster showed the fastest progression towards insulin requirement, while the MDH cluster showed the slowest progression.
Clusters based on C-peptide instead of HOMA2 measures resemble those based on HOMA2 measures, especially for SIDD, SIRD and MOD. By adding HDL-cholesterol, the MARD cluster based upon HOMA2 measures resulted in the current clustering into two clusters, with one cluster having high HDL levels. Cross-validation between cohorts showed generally a good resemblance between cohorts. Together, our results show that the clustering based on clinical variables readily measured in the clinic (age, HbA1c, HDL-cholesterol, BMI and C-peptide) results in informative clusters that are representative of the original ANDIS clusters and stable across cohorts. Adding HDL-cholesterol to the clustering resulted in the identification of a cluster with very slow glycaemic deterioration.

Link: doi.org/10.1007/s00125-021-05490-8

publications
human, blood, clinical, biomarker, diabetes
74
Article

Exosome Characterization for Targeted Drug Delivery

Henri Deda, Nuala Del Piccolo

Exosomes – or, nanometer-sized particles derived from the lipid membranes of cells – play an integral role in communication between cells and organs in the human body. These particles consist of a lipid shell surrounding cargo, which is delivered to specific sites in the body and alters the function of the recipient cell. Exosome-mediated communication has been implicated in the immune response, cancer, and neurodegeneration. Recently, exosomes have attracted the attention of scientists studying targeted drug delivery. These scientists hope to adapt exosomes to deliver therapies, instead of their natural cargo, to specific cells. For example, these reengineered exosomes might deliver a vaccine to stimulate the immune system or a chemotherapy drug to a breast cancer cell but not the surrounding healthy tissue. However, attempts to reengineer exosomes for targeted drug delivery have met with limited success to date.

Link: lipotype.com/exosomes-lipidomics-for-drug-delivery

articles
other mammals, pharma, milk
75
PNAS

LXR directly regulates glycosphingolipid synthesis and affects human CD4+ T cell function

Kirsty E Waddington, George A Robinson, Beatriz Rubio-Cuesta, Eden Chrifi-Alaoui, Sara Andreone, Kok-Siong Poon, Iveta Ivanova, Lucia Martin-Gutierrez, Dylan M Owen, Elizabeth C Jury, Inés Pineda-Torra

The liver X receptor (LXR) is a key transcriptional regulator of cholesterol, fatty acid, and phospholipid metabolism. Dynamic remodeling of immunometabolic pathways, including lipid metabolism, is a crucial step in T cell activation. Here, we explored the role of LXR-regulated metabolic processes in primary human CD4+ T cells and their role in controlling plasma membrane lipids (glycosphingolipids and cholesterol), which strongly influence T cell immune signaling and function. Crucially, we identified the glycosphingolipid biosynthesis enzyme glucosylceramide synthase as a direct transcriptional LXR target. LXR activation by agonist GW3965 or endogenous oxysterol ligands significantly altered the glycosphingolipid:cholesterol balance in the plasma membrane by increasing glycosphingolipid levels and reducing cholesterol. Consequently, LXR activation lowered plasma membrane lipid order (stability), and an LXR antagonist could block this effect. LXR stimulation also reduced lipid order at the immune synapse and accelerated activation of proximal T cell signaling molecules. Ultimately, LXR activation dampened proinflammatory T cell function. Finally, compared with responder T cells, regulatory T cells had a distinct pattern of LXR target gene expression corresponding to reduced lipid order. This suggests LXR-driven lipid metabolism could contribute to functional specialization of these T cell subsets. Overall, we report a mode of action for LXR in T cells involving the regulation of glycosphingolipid and cholesterol metabolism and demonstrate its relevance in modulating T cell function.

Link: doi.org/10.1073/pnas.2017394118

publications
human, cells, immuno
76
MDPI Cells

Different Lipid Signature in Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders

Khaled I Alatibi, Judith Hagenbuchner, Zeinab Wehbe, Daniela Karall, Michael J Ausserlechner, Jerry Vockley, Ute Spiekerkoetter, Sarah C Grünert, Sara Tucci

Long-chain fatty acid oxidation disorders (lc-FAOD) are a group of diseases affecting the degradation of long-chain fatty acids. In order to investigate the disease specific alterations of the cellular lipidome, we performed undirected lipidomics in fibroblasts from patients with carnitine palmitoyltransferase II, very long-chain acyl-CoA dehydrogenase, and long-chain 3-hydroxyacyl-CoA dehydrogenase. We demonstrate a deep remodeling of mitochondrial cardiolipins. The aberrant phosphatidylcholine/phosphatidylethanolamine ratio and the increased content of plasmalogens and of lysophospholipids support the theory of an inflammatory phenotype in lc-FAOD. Moreover, we describe increased ratios of sphingomyelin/ceramide and sphingomyelin/hexosylceramide in LCHAD deficiency which may contribute to the neuropathic phenotype of LCHADD/mitochondrial trifunctional protein deficiency.

Link: doi.org/10.3390/cells10051239

publications
human, inflammation, cells
77
THE EMBO JOURNAL

Cellular stress promotes NOD1/2-dependent inflammation via the endogenous metabolite sphingosine-1-phosphate

Gang Pei, Joanna Zyla, Lichun He, Pedro Moura‐Alves, Heidrun Steinle, Philippe Saikali, Laura Lozza, Natalie Nieuwenhuizen, January Weiner, Hans‐Joachim Mollenkopf, Kornelia Ellwanger, Christine Arnold, Mojie Duan, Yulia Dagil, Mikhail Pashenkov, Ivo Gomperts Boneca, Thomas A Kufer, Anca Dorhoi, Stefan H E Kaufmann

Cellular stress has been associated with inflammation, yet precise underlying mechanisms remain elusive. In this study, various unrelated stress inducers were employed to screen for sensors linking altered cellular homeostasis and inflammation. We identified the intracellular pattern recognition receptors NOD1/2, which sense bacterial peptidoglycans, as general stress sensors detecting perturbations of cellular homeostasis. NOD1/2 activation upon such perturbations required generation of the endogenous metabolite sphingosine‐1‐phosphate (S1P). Unlike peptidoglycan sensing via the leucine‐rich repeats domain, cytosolic S1P directly bound to the nucleotide binding domains of NOD1/2, triggering NF‐κB activation and inflammatory responses. In sum, we unveiled a hitherto unknown role of NOD1/2 in surveillance of cellular homeostasis through sensing of the cytosolic metabolite S1P. We propose S1P, an endogenous metabolite, as a novel NOD1/2 activator and NOD1/2 as molecular hubs integrating bacterial and metabolic cues.

Link: doi.org/10.15252/embj.2020106272

publications
human, inflammation, cells, basic science
78
Article

Breast Cancer and Phospholipid Metabolism

Henri Deda

Of all breast cancer patients, 10 to 20 % are diagnosed with triple-negative breast cancer (TNBC). TNBC is a type of breast cancer that is more likely to be found in people younger than age 50, it is more aggressive, and has poorer prognosis than other types of breast cancer. The growth of triple-negative breast cancer is not fueled by estrogen, progesterone, or the HER2 protein. Thus, it does not respond to hormonal therapies based on estrogen or progesterone receptors or medications targeting the HER2 protein receptors – it is triple negative. Though other medicines exist, new therapeutic approaches for TNBC are required to improve treatment quality. Targeting lipid metabolism, specifically phospholipid metabolism, has been shown a promising breast cancer research subject. Lipidomics analysis revealed a mechanism for how interfering with phospholipid metabolism inhibits tumor growth of TNBC – in vitro and in vivo. The results serve as a starting point for new medications and treatment methods against triple-negative breast cancer.

Link: lipotype.com/breast-cancer-lipid-metabolism

articles
human, cells, cancer
79
Nature Communications

Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1

Alexander Beatty, Tanu Singh, Yulia Y Tyurina, Vladimir A Tyurin, Svetlana Samovich, Emmanuelle Nicolas, Kristen Maslar, Yan Zhou, Kathy Q Cai, Yinfei Tan, Sebastian Doll, Marcus Conrad, Aravind Subramanian, Hülya Bayır, Valerian E Kagan, Ulrike Rennefahrt, Jeffrey R Peterson

Ferroptosis is associated with lipid hydroperoxides generated by the oxidation of polyunsaturated acyl chains. Lipid hydroperoxides are reduced by glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, the therapeutic potential of triggering ferroptosis in cancer cells with polyunsaturated fatty acids is unknown. Here, we identify conjugated linoleates including α-eleostearic acid (αESA) as ferroptosis inducers. αESA does not alter GPX4 activity but is incorporated into cellular lipids and promotes lipid peroxidation and cell death in diverse cancer cell types. αESA-triggered death is mediated by acyl-CoA synthetase long-chain isoform 1, which promotes αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppresses ferroptosis triggered by αESA but not by GPX4 inhibition. Oral administration of tung oil, naturally rich in αESA, to mice limits tumor growth and metastasis with transcriptional changes consistent with ferroptosis. Overall, these findings illuminate a potential approach to ferroptosis, complementary to GPX4 inhibition.

Link: doi.org/10.1038/s41467-021-22471-y

publications
human, organ/tissue, mouse, cells, pharma, cancer
80
Alzheimer's Research & Therapy

An integrative multi-omics approach reveals new central nervous system pathway alterations in Alzheimer’s disease

Christopher Clark, Loïc Dayon, Mojgan Masoodi, Gene L Bowman, Julius Popp

Multiple pathophysiological processes have been described in Alzheimer’s disease (AD). Their inter-individual variations, complex interrelations, and relevance for clinical manifestation and disease progression remain poorly understood. We hypothesize that specific molecular patterns indicating both known and yet unidentified pathway alterations are associated with distinct aspects of AD pathology. We performed multi-level cerebrospinal fluid (CSF) omics in a well-characterized cohort of older adults with normal cognition, mild cognitive impairment, and mild dementia. Proteomics, metabolomics, lipidomics, one-carbon metabolism, and neuroinflammation related molecules were analyzed at single-omic level with correlation and regression approaches. Multi-omics factor analysis was used to integrate all biological levels. Identified analytes were used to construct best predictive models of the presence of AD pathology and of cognitive decline with multifactorial regression analysis. Pathway enrichment analysis identified pathway alterations in AD. Multi-omics integration identified five major dimensions of heterogeneity explaining the variance within the cohort and differentially associated with AD. Further analysis exposed multiple interactions between single ‘omics modalities and distinct multi-omics molecular signatures differentially related to amyloid pathology, neuronal injury, and tau hyperphosphorylation. Enrichment pathway analysis revealed overrepresentation of the hemostasis, immune response, and extracellular matrix signaling pathways in association with AD. Finally, combinations of four molecules improved prediction of both AD (protein 14-3-3 zeta/delta, clusterin, interleukin-15, and transgelin-2) and cognitive decline (protein 14-3-3 zeta/delta, clusterin, cholesteryl ester 27:1 16:0 and monocyte chemoattractant protein-1). Applying an integrative multi-omics approach we report novel molecular and pathways alterations associated with AD pathology. These findings are relevant for the development of personalized diagnosis and treatment approaches in AD.

Link: doi.org/10.1186/s13195-021-00814-7

publications
human, clinical, biomarker, csf, neuro
81
Article

Lipid Profiles of Neurons and Glia Cells

Henri Deda

The mammalian brain is the second-most lipid-rich organ. About 75% of all mammalian lipid species are exclusively found in neural tissues. In their variety, lipids contribute to the morphological and functional diversity of the central nervous system consisting of neurons and glia cells. Neurons transport information to other cells. Glia cells include oligodendrocytes, astrocytes, and microglia. The primary function of oligodendrocytes is to generate myelin. Astrocytes recycle neurotransmitters, shape synaptic circuits, and maintain the blood-brain barrier. Microglia are related to immune responses and brain homeostasis. A cell-type-resolved lipid profile of the mouse brain found clear differences in lipid composition and lipid metabolism of neurons, oligodendrocytes, astrocytes, and microglia. These profiles serve as an atlas for further research of the human brain, its diseases and mental disorders.

Link: lipotype.com/lipids-of-neurons-glia-cells

articles
mouse, cells, neuro
82
Patent

Skin Care Composition Comprising Mevalonolactone

Heli Anglenius, Carole Gherardi, Laura T M Huuskonen, Juho Järvinen, Henrik M Jensen, Hannu Koivikko, Jyrki Kuusisto, Tero T Mentunen, Juha Nurmi, Piera M Pericu, Pertti M Särelä, Jani Siitonen, Kirsti Tiihonen, Gregory M Whited

The skin functions as a barrier protecting the organism from drying out as well as protecting the organism against the penetration of external, often harmful, substances. The human skin consists of two main layers of cells, epidermis and dermis. The epidermis constitutes the outermost layer of the skin and is mainly formed of terminally differentiated keratinocytes and lipids, living dividing keratinocytes located beneath the terminally differentiated ones. The outer layer of the epidermis is the part which is in contact with the environment and the particular structure of the horny layer protects the skin as well as stabilizes its own flexibility by binding a defined amount of water. The main function of the epidermis is to form permeability barrier against environmental challenges, such as UV radiation, heat, chemicals, pollution, and pathogens, such as bacteria, fungi, parasites, and viruses. It also protects the body from uncontrolled water evaporation from inside out, maintaining the hydration balance and skin metabolism. In the dermis, the most abundant cell type, dermal fibroblasts, are responsible of generating the connective tissue by producing extracellular matrix (ECM). This ECM is composed of two main classes of macromolecules: proteoglycans (PGs) and fibrous proteins; the most abundant fibrous proteins are type I collagen fibrils, elastins, laminins and fibronectins. During aging the collagen fibrils become fragmented, fibroblasts produce less ECM proteins and more ECM degrading matrix metalloproteinases (MMPs), that leads to imbalance in the ECM. There remains a need to find methods and compositions for providing skin benefits, such as but not limiting to methods and compositions for providing a skin care benefit selected from the group consisting of skin moisturizing, skin exfoliation (also referred to as skin peeling, desquamation, skin shedding, skin resurfacing, skin regeneration, skin renewal, improving epidermal cell turnover, preventing or retarding the appearance of the signs of aging of the skin (anti-aging), reducing the appearance of skin wrinkles, skin rejuvenation, strengthening the skin barrier function, or any one combination thereof) to a skin. In this patent, compositions and methods are provided for topical applications for skin care, skin supplement, hair care, oral care, comprising mevalonolactone, mevalonic acid, mevalonate, salts of mevalonic acid, mevalonolactone monohydrate, or any combination thereof.

Link: freepatentsonline.com/WO2021041363A1.html

patents
human, skin, cosmetics
83
Journal of the American Academy of Child & Adolescent Psychiatry

Adverse Effects of Refeeding on the Plasma Lipidome in Young Individuals With Anorexia Nervosa?

Friederike I Tam, Mathias J Gerl, Christian Klose, Michal A Surma, Joseph A King, Maria Seidel, Kerstin Weidner, Veit Roessner, Kai Simons, Stefan Ehrlich

Refeeding is the cornerstone of anorexia nervosa (AN) treatment, but little is known regarding the optimal pace and dietary composition or possible adverse effects of current clinical practices. Plasma lipids may be a moderating factor underlying unfavorable refeeding effects in AN, such as an abnormal central body fat distribution. The objective of this study was to analyze the plasma lipidome in the acutely underweight state of AN before and after refeeding. Using high-throughput quantitative mass spectrometry-based shotgun lipidomics, we measured 13 lipid classes and 204 lipid species or subspecies in the plasma of young female patients with acute AN, before (n=39) and after short-term weight restoration during an intensive inpatient refeeding program (n=23, median BMI increase 26.4%), in comparison to healthy control participants (n=37). Before inpatient treatment, patients with AN exhibited increased concentrations of cholesterol and several other lipid classes. After refeeding, multiple lipid classes including cholesterol and ceramides as well as certain ceramide species previously associated with obesity or overfeeding showed increased concentrations, and a pattern of shorter and more saturated triacylgycerides emerged. A machine learning model trained to predict BMI based on the lipidomic profiles revealed a sizable overprediction in patients with AN after weight restoration. The results point towards a profound lipid dysregulation with similarities to obesity and other features of the metabolic syndrome after short-term weight restoration. Thus, this study provides evidence for possible short-term adverse effects of current refeeding practices on the metabolic state and should inspire more research on nutritional interventions in AN.

Link: doi.org/10.1016/j.jaac.2021.02.014

publications
human, plasma/serum, clinical, diet, neuro, obesity
84
nature metabolism

Diet-dependent regulation of TGFβ impairs reparative innate immune responses after demyelination

Mar Bosch-Queralt, Ludovico Cantuti-Castelvetri, Alkmini Damkou, Martina Schifferer, Kai Schlepckow, Ioannis Alexopoulos, Dieter Lütjohann, Christian Klose, Lenka Vaculčiaková, Takahiro Masuda, Marco Prinz, Kathryn M Monroe, Gilbert Di Paolo, Joseph W Lewcock, Christian Haass, Mikael Simons

Proregenerative responses are required for the restoration of nervous-system functionality in demyelinating diseases such as multiple sclerosis (MS). Yet, the limiting factors responsible for poor CNS repair are only partially understood. Here, we test the impact of a Western diet (WD) on phagocyte function in a mouse model of demyelinating injury that requires microglial innate immune function for a regenerative response to occur. We find that WD feeding triggers an ageing-related, dysfunctional metabolic response that is associated with impaired myelin-debris clearance in microglia, thereby impairing lesion recovery after demyelination. Mechanistically, we detect enhanced transforming growth factor beta (TGFβ) signalling, which suppresses the activation of the liver X receptor (LXR)-regulated genes involved in cholesterol efflux, thereby inhibiting phagocytic clearance of myelin and cholesterol. Blocking TGFβ or promoting triggering receptor expressed on myeloid cells 2 (TREM2) activity restores microglia responsiveness and myelin-debris clearance after demyelinating injury. Thus, we have identified a druggable microglial immune checkpoint mechanism regulating the microglial response to injury that promotes remyelination.

Link: doi.org/10.1038/s42255-021-00341-7

publications
mouse, cells, diet, neuro
85
Communications Biology

Lipidomic and in-gel analysis of maleic acid co-polymer nanodiscs reveals differences in composition of solubilized membranes

Marta Barniol-Xicota, Steven H L Verhelst

Membrane proteins are key in a large number of physiological and pathological processes. Their study often involves a prior detergent solubilization step, which strips away the membrane and can jeopardize membrane protein integrity. A recent alternative to detergents encompasses maleic acid based copolymers (xMAs), which disrupt the lipid bilayer and form lipid protein nanodiscs (xMALPs) soluble in aqueous buffer. Although xMALPs are often referred to as native nanodiscs, little is known about the resemblance of their lipid and protein content to the native bilayer. Here we have analyzed prokaryotic and eukaryotic xMALPs using lipidomics and in-gel analysis. Our results show that the xMALPs content varies with the chemical properties of the used xMA.

Link: doi.org/10.1038/s42003-021-01711-3

publications
organelle, bacteria, method
86
Article

Lipid Biomarkers for Multiple Sclerosis

Henri Deda

In multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the central nervous system, the body attacks the protective myelin sheath of neurons in the brain and the spinal cord. The damaged myelin causes communication problems between the central nervous system and the rest of the body. To this day, there is no cure for MS. Neurobiological researchers believe that MS does not only cause the clinical symptoms we look for as of today but also alters a patient’s lipid metabolism. Detailed, molecular lipid analysis can discover specific biomarkers for MS to support fast and accurate diagnosis, better treatment, and monitoring.

Link: lipotype.com/lipid-biomarkers-for-multiple-sclerosis

articles
human, inflammation, plasma/serum, clinical, biomarker, neuro, immuno
87
International Journal of Cardiology

A plasma lipid signature predicts incident coronary artery disease

Filip Ottosson, Payam Emami Khoonsari, Mathias J Gerl, Kai Simons, Olle Melander, Céline Fernandez

Dyslipidemia is a hallmark of cardiovascular disease but is characterized by crude measurements of triglycerides, HDL- and LDL cholesterol. Lipidomics enables more detailed measurements of plasma lipids, which may help improve risk stratification and understand the pathophysiology of cardiovascular disease. Lipidomics was used to measure 184 lipids in plasma samples from the Malmö Diet and Cancer – Cardiovascular Cohort (N = 3865), taken at baseline examination. During an average follow-up time of 20.3 years, 536 participants developed coronary artery disease (CAD). Least absolute shrinkage and selection operator (LASSO) were applied to Cox proportional hazards models in order to identify plasma lipids that predict CAD. Eight plasma lipids improved prediction of future CAD on top of traditional cardiovascular risk factors. Principal component analysis of CAD-associated lipids revealed one principal component (PC2) that was associated with risk of future CAD (HR per SD increment =1.46, C·I = 1.35–1.48, P < 0.001). The risk increase for being in the highest quartile of PC2 (HR = 2.33, P < 0.001) was higher than being in the top quartile of systolic blood pressure. Addition of PC2 to traditional risk factors achieved an improvement (2%) in the area under the ROC-curve for CAD events occurring within 10 (P = 0.03), 15 (P = 0.003) and 20 (P = 0.001) years of follow-up respectively. A lipid pattern improved CAD prediction above traditional risk factors, highlighting that conventional lipid-measures insufficiently describe dyslipidemia that is present years before CAD. Identifying this hidden dyslipidemia may help motivate lifestyle and pharmacological interventions early enough to reach a substantial reduction in absolute risk.

Link: doi.org/10.1016/j.ijcard.2021.01.059

publications
human, plasma/serum, clinical, biomarker, cvd
88
EBioMedicine

Early signature in the blood lipidome associated with subsequent cognitive decline in the elderly: A case-control analysis nested within the Three-City cohort study

Sophie Lefèvre-Arbogast, Boris P Hejblum, Catherine Helmer, Christian Klose, Claudine Manach, Dorrain Y Low, Mireia Urpi-Sarda, Cristina Andres-Lacueva, Raúl González-Domínguez, Ludwig Aigner, Barbara Altendorfer, Paul J Lucassen, Silvie R Ruigrok, Chiara De Lucia, Andrea Du Preez, Cécile Proust-Lima, Sandrine Thuret, Aniko Korosi, Cécilia Samieri

Brain lipid metabolism appears critical for cognitive aging, but whether alterations in the lipidome relate to cognitive decline remains unclear at the system level. We studied participants from the Three-City study, a multicentric cohort of older persons, free of dementia at time of blood sampling, and who provided repeated measures of cognition over 12 subsequent years. We measured 189 serum lipids from 13 lipid classes using shotgun lipidomics in a case-control sample on cognitive decline (matched on age, sex and level of education) nested within the Bordeaux study center (discovery, n = 418). Associations with cognitive decline were investigated using bootstrapped penalized regression, and tested for validation in the Dijon study center (validation, n = 314). Among 17 lipids identified in the discovery stage, lower levels of the triglyceride TAG 50:5, and of four membrane lipids (sphingomyelin SM 40:2,2, phosphatidylethanolamine PE 38:5(18:1/20:4), ether-phosphatidylethanolamine PE O- 34:3(16:1/18:2), and ether-phosphatidylcholine PC O- 34:1(16:1/18:0)), and higher levels of PC O- 32:0(16:0/16:0), were associated with greater odds of cognitive decline, and replicated in our validation sample. These findings indicate that in the blood lipidome of non-demented older persons, a specific profile of lipids involved in membrane fluidity, myelination, and lipid rafts, is associated with subsequent cognitive decline.

Link: doi.org/10.1016/j.ebiom.2021.103216

publications
human, aging, plasma/serum, clinical, biomarker, neuro
89
International Journal of Molecular Sciences

Influence of Antiplatelet Agents on the Lipid Composition of Platelet Plasma Membrane: A Lipidomics Approach with Ticagrelor and Its Active Metabolite

Jennifer Lagoutte-Renosi, Florentin Allemand, Christophe Ramseyer, Vahideh Rabani, Siamak Davani

Lipids contained in the plasma membrane of platelets play an important role in platelet function. Modifications in the lipid composition can fluidify or rigidify the environment around embedded receptors, in order to facilitate the access of the receptor by the drug. However, data concerning the lipid composition of platelet plasma membrane need to be updated. In addition, data on the impact of drugs on plasma membrane composition, in particular antiplatelet agents, remain sparse. After isolation of platelet plasma membrane, we assessed, using lipidomics, the effect of ticagrelor, a P2Y12 antagonist, and its active metabolite on the lipid composition of these plasma membranes. We describe the exact lipid composition of plasma membrane, including all sub-species. Ticagrelor and its active metabolite significantly increased cholesterol and phosphatidylcholine ether with short saturated acyl chains 16:0/16:0, and decreased phosphatidylcholine, suggesting overall rigidification of the membrane. Furthermore, ticagrelor and its active metabolite decreased some arachidonylated plasmalogens, suggesting a decrease in availability of arachidonic acid from the membrane phospholipids for synthesis of biologically active mediators. To conclude, ticagrelor and its active metabolite seem to influence the lipid environment of receptors embedded in the lipid bilayer and modify the behavior of the plasma membrane.

Link: doi.org/10.3390/ijms22031432

publications
human, plasma/serum, pharma, cvd
90
Cell Reports

Genome-wide CRISPR-Cas9 knockout library screening identified PTPMT1 in cardiolipin synthesis is crucial to survival in hypoxia in liver cancer

Macus H Bao, Chunxue Yang, Aki P Tse, Lai Wei, Derek Lee, Misty S Zhang, Chi C Goh, David K Chiu, Vincent W Yuen, Cheuk-Ting Law, Wai-Ching Chin, Noreen N Chui, Bowie P Wong, Cerise Y Chan, Irene O Ng, Clive Y Chung, Chun-Ming Wong, Carmen C Wong

Hypoxia, low oxygen (O2), is a key feature of all solid cancers, including hepatocellular carcinoma (HCC). Genome-wide CRISPR-Cas9 knockout library screening is used to identify reliable therapeutic targets responsible for hypoxic survival in HCC. We find that protein-tyrosine phosphatase mitochondrial 1 (PTPMT1), an important enzyme for cardiolipin (CL) synthesis, is the most significant gene and ranks just after hypoxia-inducible factor (HIF)-1α and HIF-1β as crucial to hypoxic survival. CL constitutes the mitochondrial membrane and ensures the proper assembly of electron transport chain (ETC) complexes for efficient electron transfer in respiration. ETC becomes highly unstable during hypoxia. Knockout of PTPMT1 stops the maturation of CL and impairs the assembly of ETC complexes, leading to further electron leakage and ROS accumulation at ETC in hypoxia. Excitingly, HCC cells, especially under hypoxic conditions, show great sensitivity toward PTPMT1 inhibitor alexidine dihydrochloride (AD). This study unravels the protective roles of PTPMT1 in hypoxic survival and cancer development.

Link: doi.org/10.1016/j.celrep.2020.108676

publications
human, organ/tissue, mouse, cells, cancer
91
Article

Multiomics in Cardiovascular Disease Research

Henri Deda

Cardiovascular diseases are the leading cause of death worldwide. This group of conditions – which includes arrhythmia and heart failure – are indicated by a reduced ability of the heart and blood vessels to move blood throughout the body. Risk factors for cardiovascular disease include genetics, diet, and physical inactivity; symptoms include stroke and heart attack. Plasma lipids such as cholesterols, triglycerides, and lipoproteins are often used to estimate an individual’s risk of developing cardiovascular diseases. While informative, a more comprehensive picture of the plasma lipidome – especially if combined with other omic endpoints – may improve prediction of and inform therapies for cardiovascular diseases.

Link: lipotype.com/multiomics-in-cardiovascular-research

articles
human, plasma/serum, clinical, biomarker, cvd
92
Cell Chemical Biology

Investigating the mechanism of action of aggregation-inducing antimicrobial Pept-ins

Guiqin Wu, Laleh Khodaparast, Ladan Khodaparast, Matthias De Vleeschouwer, Joëlle Housmans, Bert Houben, Joost Schymkowitz, Frederic Rousseau

Aggregation can be selectively induced by aggregation-prone regions (APRs) contained in the target proteins. Aggregation-inducing antimicrobial peptides (Pept-ins) contain sequences homologous to APRs of target proteins and exert their bactericidal effect by causing aggregation of a large number of proteins. To better understand the mechanism of action of Pept-ins and the resistance mechanisms, we analyzed the phenotypic, lipidomic, and transcriptomic as well as genotypic changes in laboratory-derived Pept-in-resistant E. coli mutator cells. The analysis showed that the Pept-in resistance mechanism is dominated by a decreased Pept-in uptake, in both laboratory-derived mutator cells and clinical isolates. Our data indicate that Pept-in uptake involves an electrostatic attraction between the Pept-in and the bacterial membrane and follows a complex mechanism potentially involving many transporters. Furthermore, it seems more challenging for bacteria to become resistant toward Pept-ins that are less dependent on electrostatic attraction for uptake, suggesting that future Pept-ins should be selected for this property.

Link: doi.org/10.1016/j.chembiol.2020.12.008

publications
cells, bacteria, basic science
93
Cell Reports Medicine

A 4-Aminoquinoline Inhibits the Trained Innate Immune Response to Interferons

Nils Rother, Cansu Yanginlar, Rik G H Lindeboom, Siroon Bekkering, Mandy M T van Leent, Baranca Buijsers, Inge Jonkman, Mark de Graaf, Marijke Baltissen, Lieke A Lamers, Niels P Riksen, Zahi A Fayad, Willem J M Mulder, Luuk B Hilbrands, Leo A B Joosten, Mihai G Netea, Michiel Vermeulen, Johan van der Vlag, Raphaël Duivenvoorden

A commercially available 4-aminoquinoline is being investigated for a potential prophylactic effect in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but its mechanism of action is poorly understood. Circulating leukocytes from the blood of coronavirus disease 2019 (COVID-19) patients show increased responses to Toll-like receptor ligands, suggestive of trained immunity. By analyzing interferon responses of peripheral blood mononuclear cells from healthy donors conditioned with heat-killed Candida, trained innate immunity can be modeled in vitro. In this model, the 4-aminoquinoline inhibits the responsiveness of these innate immune cells to virus-like stimuli and interferons. This is associated with a suppression of histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation of inflammation-related genes, changes in the cellular lipidome, and decreased expression of interferon-stimulated genes. Our findings indicate that the 4-aminoquinoline inhibits trained immunity in vitro, which may not be beneficial for the antiviral innate immune response to SARS-CoV-2 infection in patients.

Link: doi.org/10.1016/j.xcrm.2020.100146

publications
human, clinical, cells, pharma, immuno
94
Article

Ceramide Analysis in Moisturizer Research

Henri Deda

Moisturization has taken center stage in skin care research and product development for decades. New remedies for dry skin have entered and left the shelves of drugstores. Still, dry facial skin remains a major concern for consumers. Though skin biology is central to develop reliable moisturizers, researching the impact of the skin’s molecular profile has been lacking. Skin lipidomics is changing this.

Link: lipotype.com/skin-lipidomics-for-moisturizer-research

articles
human, skin, cosmetics
95
Frontiers in Immunology

Maturation of Monocyte-Derived DCs Leads to Increased Cellular Stiffness, Higher Membrane Fluidity, and Changed Lipid Composition

Jennifer J Lühr, Nils Alex, Lukas Amon, Martin Kräter, Markéta Kubánková, Erdinc Sezgin, Christian H K Lehmann, Lukas Heger, Gordon F Heidkamp, Ana-Sunčana Smith, Vasily Zaburdaev, Rainer A Böckmann, Ilya Levental, Michael L Dustin, Christian Eggeling, Jochen Guck, Diana Dudziak

Dendritic cells (DCs) are professional antigen-presenting cells of the immune system. Upon sensing pathogenic material in their environment, DCs start to mature, which includes cellular processes, such as antigen uptake, processing and presentation, as well as upregulation of costimulatory molecules and cytokine secretion. During maturation, DCs detach from peripheral tissues, migrate to the nearest lymph node, and find their way into the correct position in the net of the lymph node microenvironment to meet and interact with the respective T cells. We hypothesize that the maturation of DCs is well prepared and optimized leading to processes that alter various cellular characteristics from mechanics and metabolism to membrane properties. Here, we investigated the mechanical properties of monocyte-derived dendritic cells (moDCs) using real-time deformability cytometry to measure cytoskeletal changes and found that mature moDCs were stiffer compared to immature moDCs. These cellular changes likely play an important role in the processes of cell migration and T cell activation. As lipids constitute the building blocks of the plasma membrane, which, during maturation, need to adapt to the environment for migration and DC-T cell interaction, we performed an unbiased high-throughput lipidomics screening to identify the lipidome of moDCs. These analyses revealed that the overall lipid composition was significantly changed during moDC maturation, even implying an increase of storage lipids and differences of the relative abundance of membrane lipids upon maturation. Further, metadata analyses demonstrated that lipid changes were associated with the serum low-density lipoprotein (LDL) and cholesterol levels in the blood of the donors. Finally, using lipid packing imaging we found that the membrane of mature moDCs revealed a higher fluidity compared to immature moDCs. This comprehensive and quantitative characterization of maturation associated changes in moDCs sets the stage for improving their use in clinical application.

Link: doi.org/10.3389/fimmu.2020.590121

publications
human, cells, immuno
96
European Journal of Pharmaceutics and Biopharmaceutics

Evaluation of Bovine Milk Extracellular Vesicles for the Delivery of Locked Nucleic Acid Antisense Oligonucleotides

Philip Grossen, Michaela Portmann, Erich Koller, Martina Duschmalé, Tanja Minz, Sabine Sewing, Nikhil J Pandya, Sabine Kux van Geijtenbeek, Axel Ducret, Eric-André Kusznir, Sylwia Huber, Marco Berrera, Matthias E Lauer, Philippe Ringler, Bettina Nordbo, Marianne Lerbech Jensen, Filippo Sladojevich, Ravi Jagasia, Rainer Alex, Remo Gamboni, Michael Keller

The natural capacity of extracellular vesicles (EVs) to transport their payload to recipient cells has raised big interest to repurpose EVs as delivery vehicles for xenobiotics. In the present study, bovine milk-derived EVs (BMEVs) were investigated for their potential to shuttle locked nucleic acid-modified antisense oligonucleotides (LNA ASOs) into the systemic circulation after oral administration. To this end, a broad array of analytical methods including proteomics and lipidomics were used to thoroughly characterize BMEVs. We found that additional purification by density gradients efficiently reduced levels of non-EV associated proteins. The potential of BMEVs to functionally transfer LNA ASOs was tested using advanced in vitro systems (i.e. hPSC-derived neurons and primary human cells). A slight increase in cellular LNA ASO internalization and target gene reduction was observed when LNA ASOs were delivered using BMEVs. When dosed orally in mice, only a small fraction (about 1 % of total administered dose) of LNA ASOs was recovered in the peripheral tissues liver and kidney, however, no significant reduction in target gene expression (i.e. functional knockdown) was observed.

Link: doi.org/10.1016/j.ejpb.2020.11.012

publications
other mammals, pharma, milk
97
nature communications

ETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine

Diletta Fontana, Mario Mauri, Rossella Renso, Mattia Docci, Ilaria Crespiatico, Lisa M Røst, Mi Jang, Antonio Niro, Deborah D’Aliberti, Luca Massimino, Mayla Bertagna, Giovanni Zambrotta, Mario Bossi, Stefania Citterio, Barbara Crescenzi, Francesca Fanelli, Valeria Cassina, Roberta Corti, Domenico Salerno, Luca Nardo, Clizia Chinello, Francesco Mantegazza, Cristina Mecucci, Fulvio Magni, Guido Cavaletti, Per Bruheim, Delphine Rea, Steen Larsen, Carlo Gambacorti-Passerini, Rocco Piazza

Recurrent somatic mutations in ETNK1 (Ethanolamine-Kinase-1) were identified in several myeloid malignancies and are responsible for a reduced enzymatic activity. Here, we demonstrate in primary leukemic cells and in cell lines that mutated ETNK1 causes a significant increase in mitochondrial activity, ROS production, and Histone H2AX phosphorylation, ultimately driving the increased accumulation of new mutations. We also show that phosphoethanolamine, the metabolic product of ETNK1, negatively controls mitochondrial activity through a direct competition with succinate at mitochondrial complex II. Hence, reduced intracellular phosphoethanolamine causes mitochondria hyperactivation, ROS production, and DNA damage. Treatment with phosphoethanolamine is able to counteract complex II hyperactivation and to restore a normal phenotype.

Link: doi.org/10.1038/s41467-020-19721-w

publications
human, cells, organelle, cancer
98
BBA Molecular and Cell Biology of Lipids

LAPTM4B controls the sphingolipid and ether lipid signature of small extracellular vesicles

Andrea Dichlberger, Kecheng Zhou, Nils Bäck, Thomas Nyholm, Anders Backman, Peter Mattjus, Elina Ikonen, Tomas Blom

Lysosome Associated Protein Transmembrane 4B (LAPTM4B) is a four-membrane spanning ceramide interacting protein that regulates mTORC1 signaling. Here, we show that LAPTM4B is sorted into intraluminal vesicles (ILVs) of multivesicular endosomes (MVEs) and released in small extracellular vesicles (sEVs) into conditioned cell culture medium and human urine. Efficient sorting of LAPTM4B into ILV membranes depends on its third transmembrane domain containing a sphingolipid interaction motif (SLim). Unbiased lipidomic analysis reveals a strong enrichment of glycosphingolipids in sEVs secreted from LAPTM4B knockout cells and from cells expressing a SLim-deficient LAPTM4B mutant. The altered sphingolipid profile is accompanied by a distinct SLim-dependent co-modulation of ether lipid species. The changes in the lipid composition of sEVs derived from LAPTM4B knockout cells is reflected by an increased stability of membrane nanodomains of sEVs. These results identify LAPTM4B as a determinant of the glycosphingolipid profile and membrane properties of sEVs.

Link: doi.org/10.1016/j.bbalip.2020.158855

publications
human, cells, organelle, basic science
99
Annals of Clinical and Translational Neurology

Plasma lipidomics of monozygotic twins discordant for multiple sclerosis

Horst Penkert, Chris Lauber, Mathias J Gerl, Christian Klose, Markus Damm, Dirk Fitzner, Andrea Flierl‐Hecht, Tania Kümpfel, Martin Kerschensteiner, Reinhard Hohlfeld, Lisa A Gerdes, Mikael Simons

Blood biomarkers of multiple sclerosis (MS) can provide a better understanding of pathophysiology and enable disease monitoring. Here, we performed quantitative shotgun lipidomics on the plasma of a unique cohort of 73 monozygotic twins discordant for MS. We analyzed 243 lipid species, evaluated lipid features such as fatty acyl chain length and number of acyl chain double bonds, and detected phospholipids that were significantly altered in the plasma of co‐twins with MS compared to their non‐affected siblings. Strikingly, changes were most prominent in ether phosphatidylethanolamines and ether phosphatidylcholines, suggesting a role for altered lipid signaling in the disease.

Link: doi.org/10.1002/acn3.51216

publications
human, plasma/serum, clinical, biomarker, neuro
100
Frontiers in Cell and Developmental Biology

Fluidity and Lipid Composition of Membranes of Peroxisomes, Mitochondria and the ER From Oleic Acid-Induced Saccharomyces cerevisiae

Katharina Reglinski, Laura Steinfort-Effelsberg, Erdinc Sezgin, Christian Klose, Harald W Platta, Wolfgang Girzalsky, Christian Eggeling, Ralf Erdmann

The maintenance of a fluid lipid bilayer is key for organelle function and cell viability. Given the critical role of lipid compositions in determining membrane properties and organelle identity, it is clear that cells must have elaborate mechanism for membrane maintenance during adaptive responses to environmental conditions. Emphasis of the presented study is on peroxisomes, oleic acid-inducible organelles that are essential for the growth of yeast under conditions of oleic acid as single carbon source. Here, we isolated peroxisomes, mitochondria and ER from oleic acid-induced Saccharomyces cerevisiae and determined the lipid composition of their membranes using shotgun lipidomics and compared it to lipid ordering using fluorescence microscopy. In comparison to mitochondrial and ER membranes, the peroxisomal membranes were slightly more disordered and characterized by a distinct enrichment of phosphaditylinositol, indicating an important role of this phospholipid in peroxisomal membrane associated processes.

Link: doi.org/10.3389/fcell.2020.574363

publications
organelle, yeast, basic science
101
PNAS

Myelination of peripheral nerves is controlled by PI4KB through regulation of Schwann cell Golgi function

Takashi Baba, Alejandro Alvarez-Prats, Yeun Ju Kim, Daniel Abebe, Steve Wilson, Zane Aldworth, Mark A Stopfer, John Heuser, Tamas Balla

Better understanding myelination of peripheral nerves would benefit patients affected by peripheral neuropathies, including Charcot–Marie–Tooth disease. Little is known about the role the Golgi compartment plays in Schwann cell (SC) functions. Here, we studied the role of Golgi in myelination of peripheral nerves in mice through SC-specific genetic inactivation of phosphatidylinositol 4-kinase beta (PI4KB), a Golgi-associated lipid kinase. Sciatic nerves of such mice showed thinner myelin of large diameter axons and gross aberrations in myelin organization affecting the nodes of Ranvier, the Schmidt–Lanterman incisures, and Cajal bands. Nonmyelinating SCs showed a striking inability to engulf small diameter nerve fibers. SCs of mutant mice showed a distorted Golgi morphology and disappearance of OSBP at the cis-Golgi compartment, together with a complete loss of GOLPH3 from the entire Golgi. Accordingly, the cholesterol and sphingomyelin contents of sciatic nerves were greatly reduced and so was the number of caveolae observed in SCs. Although the conduction velocity of sciatic nerves of mutant mice showed an 80% decrease, the mice displayed only subtle impairment in their motor functions. Our analysis revealed that Golgi functions supported by PI4KB are critically important for proper myelination through control of lipid metabolism, protein glycosylation, and organization of microvilli in the nodes of Ranvier of peripheral nerves.

Link: doi.org/10.1073/pnas.2007432117

publications
organ/tissue, mouse, neuro
102
Patent

Methods and Compositions Relating to Chondrisomes from Cultured Cells

Geoffrey A Von Maltzahn, John M Milwid, Michael T Mee, Jacob Rosenblum-Rubens, David Chess, Kyle M Trudeau, Kiana Mahdaviani, Jacob Feala

Mitochondria are membrane bound subcellular structures found in eukaryotic cells. Sometimes described as the power plants of cells, mitochondria generate most of the energy of the cell in the form of adenosine triphosphate (ATP) through respiration. Damage and subsequent dysfunction of mitochondria are important factors in a range of human diseases. Described herein are novel preparations of chondrisomes derived from mitochondria, and related methods, that have advantageous and surprising qualities for use in human pharmaceutical and in veterinary applications. Chondrisome preparations and methods described herein have beneficial structural characteristics, yield, concentration, stability, viability, integrity, or function, e.g., a bioenergetic or biological function, for use in therapeutic applications. Accordingly, in one aspect, the invention features a pharmaceutical composition comprising a preparation of isolated chondrisomes, derived from cultured cells, and a pharmaceutically acceptable carrier.

Link: freepatentsonline.com/y2020/0306315.html

patents
human, organelle, pharma, method
103
Patent

Methods and Compositions Relating to Chondrisomes from Blood Products

Geoffrey A Von Maltzahn, John M Milwid, Michael T Mee, Jacob Rosenblum-Rubens, David Chess, Kyle M Trudeau, Kiana Mahdaviani, Jacob Feala

Mitochondria are membrane bound subcellular structures found in eukaryotic cells. Sometimes described as the power plants of cells, mitochondria generate most of the energy of the cell in the form of adenosine triphosphate (ATP) through respiration. Damage and subsequent dysfunction of mitochondria are important factors in a range of human diseases. Described herein are novel preparations of chondrisomes derived from blood or blood products, and related methods, that have advantageous and surprising qualities for use in human pharmaceutical and in veterinary applications. Chondrisome and mitoparticle preparations and methods described herein have beneficial structural characteristics, yield, concentration, stability, viability, integrity, or function, e.g., a bioenergetic or biological function, for use in therapeutic applications. Accordingly, in one aspect, the invention features a pharmaceutical composition comprising a preparation of isolated chondrisomes and/or mitoparticles, derived from blood or a blood product, and a pharmaceutically acceptable carrier.

Link: freepatentsonline.com/y2020/0306316.html

patents
human, organelle, pharma, method
104
eLife

Phosphatidylcholines from Pieris brassicae eggs activate an immune response in Arabidopsis

Elia Stahl, Théo Brillatz, Emerson Ferreira Queiroz, Laurence Marcourt, André Schmiesing, Olivier Hilfiker, Isabelle Riezman, Howard Riezman, Jean-Luc Wolfender, Philippe Reymond

Recognition of conserved microbial molecules activates immune responses in plants, a process termed pattern-triggered immunity (PTI). Similarly, insect eggs trigger defenses that impede egg development or attract predators, but information on the nature of egg-associated elicitors is scarce. We performed an unbiased bioactivity-guided fractionation of eggs of the butterfly Pieris brassicae. Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry of active fractions led to the identification of phosphatidylcholines (PCs). PCs are released from insect eggs, and they induce salicylic acid and H2O2 accumulation, defense gene expression and cell death in Arabidopsis, all of which constitute a hallmark of PTI. Active PCs contain primarily C16 to C18-fatty acyl chains with various levels of desaturation, suggesting a relatively broad ligand specificity of cell-surface receptor(s). The finding of PCs as egg-associated molecular patterns (EAMPs) illustrates the acute ability of plants to detect conserved immunogenic patterns from their enemies, even from seemingly passive structures such as eggs.

Link: doi.org/10.7554/eLife.60293

publications
cells, insects, agriculture
105
Cell Reports

Cell-Type- and Brain-Region-Resolved Mouse Brain Lipidome

Dirk Fitzner, Jakob M Bader, Horst Penkert, Caroline G Bergner, Minhui Su, Marie-Theres Weil, Michal A Surma, Matthias Mann, Christian Klose, Mikael Simons

Gene and protein expression data provide useful resources for understanding brain function, but little is known about the lipid composition of the brain. Here, we perform quantitative shotgun lipidomics, which enables a cell-type-resolved assessment of the mouse brain lipid composition. We quantify around 700 lipid species and evaluate lipid features including fatty acyl chain length, hydroxylation, and number of acyl chain double bonds, thereby identifying cell-type- and brain-region-specific lipid profiles in adult mice, as well as in aged mice, in apolipoprotein-E-deficient mice, in a model of Alzheimer’s disease, and in mice fed different diets. We also integrate lipid with protein expression profiles to predict lipid pathways enriched in specific cell types, such as fatty acid β-oxidation in astrocytes and sphingolipid metabolism in microglia. This resource complements existing brain atlases of gene and protein expression and may be useful for understanding the role of lipids in brain function.

Link: doi.org/10.1016/j.celrep.2020.108132

publications
mouse, cells, neuro
106
International Journal of Molecular Sciences

Tolerance of Stored Boar Spermatozoa to Autologous Seminal Plasma: A Proteomic and Lipidomic Approach

Lisa Höfner, Anne-Marie Luther, Alessandra Palladini, Thomas Fröhlich, Dagmar Waberski

Long-term exposure of liquid preserved boar spermatozoa to seminal plasma (SP) can cause dramatic sperm injury. This study examined whether boar specificity exists in the sensitivity of spermatozoa to SP and whether correspondent biomarkers can be identified. Consecutive ejaculates (n = 4–5) collected from 19 boars were centrifuged, diluted with a pH-stablising extender with 10% (v/v) autologous SP and evaluated by computer-assisted semen analysis and flow cytometry. Up until 144 h storage, four boars showed consistently high sperm motility, viability and mitochondria activity, and one boar showed consistently low values. Intra-boar variability was high in the other boars. Screening of SP (n = 12 samples) for protein markers using mass spectrometry identified three protein candidates of which the granulin precursor, legumain and AWN were 0.5 to 0.9 log2-fold less abundant (p < 0.05) in SP-resistant compared to SP-sensitive samples. Lipidome analysis by mass spectrometry revealed 568 lipids showing no difference between the SP-groups. The most abundant lipids were cholesterol (42,442 pmol), followed by phosphatidylserine (20,956 pmol) and ether-linked phosphatidylethanolamine (13,039 pmol). In conclusion, three candidate proteins were identified which might be indicative of SP-tolerance of sperm during long-term storage. Noteworthy, a first lipidomic profile of boar SP is presented.

Link: doi.org/10.3390/ijms21186474

publications
other mammals, agriculture, sperm
107
PNAS

Human epidermal stem cell differentiation is modulated by specific lipid subspecies

Matteo Vietri Rudan, Ajay Mishra, Christian Klose, Ulrike S Eggert, Fiona M Watt

While the lipids of the outer layers of mammalian epidermis and their contribution to barrier formation have been extensively described, the role of individual lipid species in the onset of keratinocyte differentiation remains unknown. A lipidomic analysis of primary human keratinocytes revealed accumulation of numerous lipid species during suspension-induced differentiation. A small interfering RNA screen of 258 lipid-modifying enzymes identified two genes that on knockdown induced epidermal differentiation: ELOVL1, encoding elongation of very long-chain fatty acids protein 1, and SLC27A1, encoding fatty acid transport protein 1. By intersecting lipidomic datasets from suspension-induced differentiation and knockdown keratinocytes, we pinpointed candidate bioactive lipid subspecies as differentiation regulators. Several of these—ceramides and glucosylceramides—induced differentiation when added to primary keratinocytes in culture. Our results reveal the potential of lipid subspecies to regulate exit from the epidermal stem cell compartment.

Link: doi.org/10.1073/pnas.2011310117

publications
human, cells, skin, basic science
108
Frontiers in Cell and Developmental Biology

A Quantitative Analysis of Cellular Lipid Compositions During Acute Proteotoxic ER Stress Reveals Specificity in the Production of Asymmetric Lipids

John Reinhard, Carsten Mattes, Kristina Väth, Toni Radanović, Michal A Surma, Christian Klose, Robert Ernst

The unfolded protein response (UPR) is central to endoplasmic reticulum (ER) homeostasis by controlling its size and protein folding capacity. When activated by unfolded proteins in the ER-lumen or aberrant lipid compositions, the UPR adjusts the expression of hundreds of target genes to counteract ER stress. The proteotoxic drugs dithiothreitol (DTT) and tunicamycin (TM) are commonly used to induce misfolding of proteins in the ER and to study the UPR. However, their potential impact on the cellular lipid composition has never been systematically addressed. Here, we report the quantitative, cellular lipid composition of Saccharomyces cerevisiae during acute, proteotoxic stress in both rich and synthetic media. We show that DTT causes rapid remodeling of the lipidome when used in rich medium at growth-inhibitory concentrations, while TM has only a marginal impact on the lipidome under our conditions of cultivation. We formulate recommendations on how to study UPR activation by proteotoxic stress without interferences from a perturbed lipid metabolism. Furthermore, our data suggest an intricate connection between the cellular growth rate, the abundance of the ER, and the metabolism of fatty acids. We show that Saccharomyces cerevisiae can produce asymmetric lipids with two saturated fatty acyl chains differing substantially in length. These observations indicate that the pairing of saturated fatty acyl chains is tightly controlled and suggest an evolutionary conservation of asymmetric lipids and their biosynthetic machineries.

Link: doi.org/10.3389/fcell.2020.00756

publications
cells, yeast, basic science
109
Article

Multi Resistant Bacteria & Phospholipids

Henri Deda

The discovery and description of the first antibiotic compound in 1928 was a milestone in pharma research, and the development of further antibiotics helped modern medicine thrive and flourish. Antibiotics prevent infections from spreading and help the immune system fight off invading pathogens like bacteria. Their wide-spread use comes with a downside: many bacteria evolved strategies to resist antibiotics thus rendering them ineffective. The development of new antibiotics alone is not believed to stop multi resistant bacteria. A new strategy is emerging.

Link: lipotype.com/lipidomics-of-multi-resistant-bacteria

articles
cells, pharma, bacteria
110
Article

Lipid-based Adjuvants in Vaccine Development

Henri Deda

Vaccines train the immune system to recognize pathogens. To achieve that, they introduce antigens to the body to trigger an immune response. Vaccine development can count on agents that enhance the impact of the antigens in the human body by triggering a stronger immune reaction with fewer antigen. These vaccine components are called adjuvants, they are the magic sauce of modern vaccines. Adjuvants are added to vaccines to boost their efficiency, but the underlying molecular mechanisms used to be poorly understood.

Link: lipotype.com/lipidomics-in-vaccine-research

articles
mouse, cells, pharma, immuno
111
Translational Oncology

Mass Spectrometry–Based Lipidomics of Oral Squamous Cell Carcinoma Tissue Reveals Aberrant Cholesterol and Glycerophospholipid Metabolism — A Pilot Study

Amy Dickinson, Mayank Saraswat, Sakari Joenväärä, Rahul Agarwal, Daniel Jyllikoski, Tommy Wilkman, Antti Mäkitie, Suvi Silén

Lipid metabolic reprogramming is one hallmark of cancer. Lipid metabolism is regulated by numerous enzymes, many of which are targeted by several drugs on the market. We aimed to characterize the lipid alterations in oral squamous cell carcinoma (OSCC) as a basis for understanding its lipid metabolism, thus identifying potential therapeutic targets. We compared lipid species, classes, and glycerophospholipid (GPL) fatty acid species between paired tumor tissue and healthy oral tongue mucosa samples from 10 OSCC patients using a QExactive mass spectrometer. After filtering the 1370 lipid species identified, we analyzed 349 species: 71 were significantly increased in OSCC. The GPL metabolism pathway was most represented by the lipids differing in OSCC (P = .005). Cholesterol and the GPLs phosphatidylcholines, phosphatidylethanolamines, and phosphatidylinositols were most significantly increased in OSCC tissue (FC 1.8, 2.0, 2.1, and 2.3 and, P = .003, P = .005, P = .002, P = .007). In conclusion, we have demonstrated a shift in the lipid metabolism in these OSCC samples by characterizing the detailed landscape. Predominantly, cholesterol and GPL metabolism were altered, suggesting that interactions with sterol regulatory binding proteins may be involved. The FA composition changes of the GPLs suggest increased de novo lipogenesis.

Link: doi.org/10.1016/j.tranon.2020.100807

publications
human, organ/tissue, clinical, cancer
112
Journal of Cellular and Molecular Medicine

Targeting lipid droplet lysophosphatidylcholine for cisplatin chemotherapy

Lumin Chen, Wen-Lung Ma, Wei-Chung Cheng, Juan-Cheng Yang, Hsiao-Ching Wang, Yu‐Ting Su, Azaj Ahmad, Yao‐Ching Hung, Wei‐Chun Chang

This study aims to explore lipidic mechanism towards low‐density lipoprotein receptor (LDLR)‐mediated platinum chemotherapy resistance. By using the lipid profiling technology, LDLR knockdown was found to increase lysosomal lipids and decrease membranous lipid levels in EOC cells. LDLR knockdown also down‐regulated ether‐linked phosphatidylethanolamine (PE‐O, lysosomes or peroxisomes) and up‐regulated lysophosphatidylcholine [LPC, lipid droplet (LD)]. This implies that the manner of using Lands cycle (conversion of lysophospholipids) for LDs might affect cisplatin sensitivity. The bioinformatics analyses illustrated that LDLR‐related lipid entry into LD, rather than an endogenous lipid resource (eg Kennedy pathway), controls the EOC prognosis of platinum chemotherapy patients. Moreover, LDLR knockdown increased the number of platinum‐DNA adducts and reduced the LD platinum amount. By using a manufactured LPC‐liposome‐cisplatin (LLC) drug, the number of platinum‐DNA adducts increased significantly in LLC‐treated insensitive cells. Moreover, the cisplatin content in LDs increased upon LLC treatment. Furthermore, lipid profiles of 22 carcinoma cells with differential cisplatin sensitivity (9 sensitive vs 13 insensitive) were acquired. These profiles revealed low storage lipid levels in insensitive cells. This result recommends that LD lipidome might be a common pathway in multiple cancers for platinum sensitivity in EOC. Finally, LLC suppressed both cisplatin‐insensitive human carcinoma cell training and testing sets. Thus, LDLR‐platinum insensitivity can be due to a defective Lands cycle that hinders LPC production in LDs. Using lipidome assessment with the newly formulated LLC can be a promising cancer chemotherapy method.

Link: doi.org/10.1111/jcmm.15218

publications
human, cells, pharma, cancer
113
Brain

Excess Lipin enzyme activity contributes to TOR1A recessive disease and DYT-TOR1A dystonia

Ana Cascalho, Joyce Foroozandeh, Lise Hennebel, Jef Swerts, Christine Klein, Stef Rous, Beatriz Dominguez Gonzalez, Antonio Pisani, Maria Meringolo, Sandra F Gallego, Patrik Verstreken, Philip Seibler, Rose E Goodchild

TOR1A/TorsinA mutations cause two incurable diseases: a recessive congenital syndrome that can be lethal, and a dominantly-inherited childhood-onset dystonia (DYT-TOR1A). TorsinA has been linked to phosphatidic acid lipid metabolism in Drosophila melanogaster. Here we evaluate the role of phosphatidic acid phosphatase (PAP) enzymes in TOR1A diseases using induced pluripotent stem cell-derived neurons from patients, and mouse models of recessive Tor1a disease. We find that Lipin PAP enzyme activity is abnormally elevated in human DYT-TOR1A dystonia patient cells and in the brains of four different Tor1a mouse models. Its severity also correlated with the dosage of Tor1a/TOR1A mutation. We assessed the role of excess Lipin activity in the neurological dysfunction of Tor1a disease mouse models by interbreeding these with Lpin1 knock-out mice. Genetic reduction of Lpin1 improved the survival of recessive Tor1a disease-model mice, alongside suppressing neurodegeneration, motor dysfunction, and nuclear membrane pathology. These data establish that TOR1A disease mutations cause abnormal phosphatidic acid metabolism, and suggest that approaches that suppress Lipin PAP enzyme activity could be therapeutically useful for TOR1A diseases.

Link: doi.org/10.1093/brain/awaa139

publications
organ/tissue, mouse, neuro
114
MDPI Cells

Phosphoinositide Profile of the Mouse Retina

Stella Finkelstein, Sidney M Gospe III, Kai Schuhmann, Andrej Shevchenko, Vadim Y Arshavsky, Ekaterina S Lobanova

Phosphoinositides are known to play multiple roles in eukaryotic cells. Although dysregulation of phosphoinositide metabolism in the retina has been reported to cause visual dysfunction in animal models and human patients, our understanding of the phosphoinositide composition of the retina is limited. Here, we report a characterization of the phosphoinositide profile of the mouse retina and an analysis of the subcellular localization of major phosphorylated phosphoinositide forms in light-sensitive photoreceptor neurons. Using chromatography of deacylated phosphatidylinositol headgroups, we established PI(4,5)P2 and PI(4)P as two major phosphorylated phosphoinositides in the retina. Using high-resolution mass spectrometry, we revealed 18:0/20:4 and 16:0/20:4 as major fatty-acyl chains of retinal phosphoinositides. Finally, analysis of fluorescent phosphoinositide sensors in rod photoreceptors demonstrated distinct subcellular distribution patterns of major phosphoinositides. The PI(4,5)P2 reporter was enriched in the inner segments and synapses, but was barely detected in the light-sensitive outer segments. The PI(4)P reporter was mostly found in the outer and inner segments and the areas around nuclei, but to a lesser degree in the synaptic region. These findings provide support for future mechanistic studies defining the biological significance of major mono- (PI(4)P) and bisphosphate (PI(4,5)P2) phosphatidylinositols in photoreceptor biology and retinal health.

Link: doi.org/10.3390/cells9061417

publications
mouse, cells, basic science
115
Scientific Reports

Avicin G is a potent sphingomyelinase inhibitor and blocks oncogenic K- and H-Ras signaling

Christian M Garrido, Karen M Henkels, Kristen M Rehl, Hong Liang, Yong Zhou, Jordan U Gutterman, Kwang-Jin Cho

K-Ras must interact primarily with the plasma membrane (PM) for its biological activity. Therefore, disrupting K-Ras PM interaction is a tractable approach to block oncogenic K-Ras activity. Here, we found that avicin G, a family of natural plant-derived triterpenoid saponins from Acacia victoriae, mislocalizes K-Ras from the PM and disrupts PM spatial organization of oncogenic K-Ras and H-Ras by depleting phosphatidylserine (PtdSer) and cholesterol contents, respectively, at the inner PM leaflet. Avicin G also inhibits oncogenic K- and H-Ras signal output and the growth of K-Ras-addicted pancreatic and non-small cell lung cancer cells. We further identified that avicin G perturbs lysosomal activity, and disrupts cellular localization and activity of neutral and acid sphingomyelinases (SMases), resulting in elevated cellular sphingomyelin (SM) levels and altered SM distribution. Moreover, we show that neutral SMase inhibitors disrupt the PM localization of K-Ras and PtdSer and oncogenic K-Ras signaling. In sum, this study identifies avicin G as a new potent anti-Ras inhibitor, and suggests that neutral SMase can be a tractable target for developing anti-K-Ras therapeutics.

Link: doi.org/10.1038/s41598-020-65882-5

publications
other mammals, cells, cancer
116
The EMBO Journal

Dysfunctional oxidative phosphorylation shunts branched‐chain amino acid catabolism onto lipogenesis in skeletal muscle

Cristina Sánchez‐González, Cristina Nuevo‐Tapioles, Juan C Herrero Martín, Marta P Pereira, Sandra Serrano Sanz, Ana Ramírez de Molina, José M Cuezva, Laura Formentini

It is controversial whether mitochondrial dysfunction in skeletal muscle is the cause or consequence of metabolic disorders. Herein, we demonstrate that in vivo inhibition of mitochondrial ATP synthase in muscle alters whole‐body lipid homeostasis. Mice with restrained mitochondrial ATP synthase activity presented intrafiber lipid droplets, dysregulation of acyl‐glycerides, and higher visceral adipose tissue deposits, poising these animals to insulin resistance. This mitochondrial energy crisis increases lactate production, prevents fatty acid β‐oxidation, and forces the catabolism of branched‐chain amino acids (BCAA) to provide acetyl‐CoA for de novo lipid synthesis. In turn, muscle accumulation of acetyl‐CoA leads to acetylation‐dependent inhibition of mitochondrial respiratory complex II enhancing oxidative phosphorylation dysfunction which results in augmented ROS production. By screening 702 FDA‐approved drugs, we identified edaravone as a potent mitochondrial antioxidant and enhancer. Edaravone administration restored ROS and lipid homeostasis in skeletal muscle and reinstated insulin sensitivity. Our results suggest that muscular mitochondrial perturbations are causative of metabolic disorders and that edaravone is a potential treatment for these diseases.

Link: doi.org/10.15252/embj.2019103812

publications
organ/tissue, mouse, cells, pharma
117
Cellular and Molecular Life Sciences

Diacylglycerol kinase and phospholipase D inhibitors alter the cellular lipidome and endosomal sorting towards the Golgi apparatus

Anne B Dyve Lingelem, Simona Kavaliauskiene, Ruth Halsne, Tove I Klokk, Michal A Surma, Christian Klose, Tore Skotland, Kirsten Sandvig

The membrane lipids diacylglycerol (DAG) and phosphatidic acid (PA) are important second messengers that can regulate membrane transport by recruiting proteins to the membrane and by altering biophysical membrane properties. DAG and PA are involved in the transport from the Golgi apparatus to endosomes, and we have here investigated whether changes in these lipids might be important for regulation of transport to the Golgi using the protein toxin ricin. Modulation of DAG and PA levels using DAG kinase (DGK) and phospholipase D (PLD) inhibitors gave a strong increase in retrograde ricin transport, but had little impact on ricin recycling or degradation. Inhibitor treatment strongly affected the endosome morphology, increasing endosomal tubulation and size. Furthermore, ricin was present in these tubular structures together with proteins known to regulate retrograde transport. Using siRNA to knock down different isoforms of PLD and DGK, we found that several isoforms of PLD and DGK are involved in regulating ricin transport to the Golgi. Finally, by performing lipidomic analysis we found that the DGK inhibitor gave a weak, but expected, increase in DAG levels, while the PLD inhibitor gave a strong and unexpected increase in DAG levels, showing that it is important to perform lipidomic analysis when using inhibitors of lipid metabolism.

Link: doi.org/10.1007/s00018-020-03551-6

publications
human, cells, basic science
118
Patent

Fusosome Compositions for Hematopoietic Stem Cell Delivery

Geoffrey A Von Maltzahn, Jacob Rosenblum-Rubens, Jagesh V Shah, Albert Ruzo Matias, Ferdinando Pucci, John M Milwid, Michael T Mee, Neal F Gordon

Complex biologies are promising therapeutic candidates for a variety of diseases. However, it is difficult to deliver large biologic agents into a cell because the plasma membrane acts as a barrier between the cell and the extracellular space. There is a need in the art for new methods of delivering complex biologies into cells in a subject. The present disclosure provides, at least in part, fusosome methods and compositions for in vivo delivery. In some embodiments, the fusosome comprises a combination of elements that promote specificity for target cells, e.g., one or more of a fusogen, a positive target cell-specific regulatory element, and a non-target cell-specific regulatory element. In some embodiments, the fusosome comprises one or more modifications that decrease an immune response against the fusosome.

Link: freepatentsonline.com/WO2020102485A1.html

patents
human, organelle, pharma, method
119
Patent

Fusosome Compositions for T Cell Delivery

Geoffrey A Von Maltzahn, Jacob Rosenblum-Rubens, Jagesh V Shah, Albert Ruzo Matias, Ferdinando Pucci, John M Milwid, Michael T Mee, Neal F Gordon

Complex biologies are promising therapeutic candidates for a variety of diseases. However, it is difficult to deliver large biologic agents into a cell because the plasma membrane acts as a barrier between the cell and the extracellular space. There is a need in the art for new methods of delivering complex biologies into cells in a subject. The present disclosure provides, at least in part, fusosome methods and compositions for in vivo delivery. In some embodiments, the fusosome comprises a combination of elements that promote specificity for target cells, e.g., one or more of a fusogen, a positive target cell-specific regulatory element, and a non-target cell-specific regulatory element. In some embodiments, the fusosome comprises one or more modifications that decrease an immune response against the fusosome.

Link: freepatentsonline.com/WO2020102503A2.html

patents
organelle, pharma, immuno, method
120
Patent

Fusosome Compositions for CNS Delivery

Geoffrey A Von Maltzahn, Jacob Rosenblum-Rubens, Jagesh V Shah, Albert Ruzo Matias, Ferdinando Pucci, John M Milwid, Michael T Mee, Neal F Gordon

Complex biologies are promising therapeutic candidates for a variety of diseases. However, it is difficult to deliver large biologic agents into a cell because the plasma membrane acts as a barrier between the cell and the extracellular space. There is a need in the art for new methods of delivering complex biologies into cells in a subject. The present disclosure provides, at least in part, fusosome methods and compositions for in vivo delivery. In some embodiments, the fusosome comprises a combination of elements that promote specificity for target cells, e.g., one or more of a fusogen, a positive target cell-specific regulatory element, and a non-target cell-specific regulatory element. In some embodiments, the fusosome comprises one or more modifications that decrease an immune response against the fusosome.

Link: freepatentsonline.com/WO2020102499A2.html

patents
organelle, pharma, neuro, method
121
Soft Matter

Lipidomic atlas of mammalian cell membranes reveals hierarchical variation induced by culture conditions, subcellular membranes, and cell lineages

Jessica L Symons, Kwang-Jin Cho, Jeffrey T Chang, Guangwei Du, M Neal Waxham, John F Hancock, Ilya Levental, Kandice R Levental

Lipid membranes are ubiquitous biological organizers, required for structural and functional compartmentalization of the cell and sub-cellular organelles. Membranes in living cells are compositionally complex, comprising hundreds of dynamically regulated, distinct lipid species. Cellular physiology requires tight regulation of these lipidomic profiles to achieve proper membrane functionality. While some general features of tissue- and organelle-specific lipid complements have been identified, less is known about detailed lipidomic variations caused by cell-intrinsic or extrinsic factors. Here, we use shotgun lipidomics to report detailed, comprehensive lipidomes of a variety of cultured and primary mammalian membrane preparations to identify trends and sources of variation. Unbiased principle component analysis (PCA) shows clear separation between cultured and primary cells, with primary erythrocytes, synaptic membranes, and other mammalian tissue lipidomes sharply diverging from all cultured cell lines and also from one other. Most broadly, cultured cell membrane preparations were distinguished by their paucity of polyunsaturated lipids. Cultured mammalian cell lines were comparatively similar to one another, although we detected clear, highly reproducible lipidomic signatures of individual cell lines and plasma membrane (PM) isolations thereof. These measurements begin to establish a comprehensive lipidomic atlas of mammalian cells and tissues, identifying some major sources of variation. These observations will allow investigation of the regulation and functional significance of mammalian lipidomes in various contexts.

Link: doi.org/10.1039/D0SM00404A

publications
human, mouse, other mammals, organelle, basic science
122
nature chemical biology

Plasma membranes are asymmetric in lipid unsaturation, packing and protein shape

Joseph H Lorent, Kandice R Levental, Lakshmi Ganesan, G Rivera-Longsworth, Erdinc Sezgin, Milka D Doktorova, Edward Lyman, Ilya Levental

A fundamental feature of cellular plasma membranes (PMs) is an asymmetric lipid distribution between the bilayer leaflets. However, neither the detailed, comprehensive compositions of individual PM leaflets nor how these contribute to structural membrane asymmetries have been defined. We report the distinct lipidomes and biophysical properties of both monolayers in living mammalian PMs. Phospholipid unsaturation is dramatically asymmetric, with the cytoplasmic leaflet being approximately twofold more unsaturated than the exoplasmic leaflet. Atomistic simulations and spectroscopy of leaflet-selective fluorescent probes reveal that the outer PM leaflet is more packed and less diffusive than the inner leaflet, with this biophysical asymmetry maintained in the endocytic system. The structural asymmetry of the PM is reflected in the asymmetric structures of protein transmembrane domains. These structural asymmetries are conserved throughout Eukaryota, suggesting fundamental cellular design principles.

Link: doi.org/10.1038/s41589-020-0529-6

publications
human, organelle, basic science
123
Cell Reports

The Mitochondrial Import Complex MIM Functions as Main Translocase for α-Helical Outer Membrane Proteins

Kim Nguyen Doan, Alexander Grevel, Christoph U Mårtensson, Lars Ellenrieder, Nicolas Thornton, Lena-Sophie Wenz, Lukasz Opaliński, Bernard Guiard, Nikolaus Pfanner, Thomas Becker

The mitochondrial outer membrane contains integral proteins with α-helical membrane anchors or a transmembrane β-barrel. The translocase of the outer membrane (TOM) cooperates with the sorting and assembly machinery (SAM) in the import of β-barrel proteins, whereas the mitochondrial import (MIM) complex inserts precursors of multi-spanning α-helical proteins. Single-spanning proteins constitute more than half of the integral outer membrane proteins; however, their biogenesis is poorly understood. We report that the yeast MIM complex promotes the insertion of proteins with N-terminal (signal-anchored) or C-terminal (tail-anchored) membrane anchors. The MIM complex exists in three dynamic populations. MIM interacts with TOM to accept precursor proteins from the receptor Tom70. Free MIM complexes insert single-spanning proteins that are imported in a Tom70-independent manner. Finally, coupling of MIM and SAM promotes early assembly steps of TOM subunits. We conclude that the MIM complex is a major and versatile protein translocase of the mitochondrial outer membrane.

Link: doi.org/10.1016/j.celrep.2020.107567

publications
organelle, yeast, basic science
124
Microbial Biotechnology

Myriocin‐induced adaptive laboratory evolution of an industrial strain of Saccharomyces cerevisiae reveals its potential to remodel lipid composition and heat tolerance

Francisca Randez‐Gil, Jose A Prieto, Alejandro Rodríguez‐Puchades, Josefina Casas, Vicente Sentandreu, Francisco Estruch

The modification of lipid composition allows cells to adjust membrane biophysical properties in response to changes in environmental temperature. Here, we use adaptive laboratory evolution (ALE) in the presence of myriocin, a sphingolipid (SLs) biosynthesis inhibitor, to remodel the lipid profile of an industrial yeast strain (LH) of Saccharomyces cerevisiae. The approach enabled to obtain a heterogeneous population (LHev) of myriocin‐tolerant evolved clones characterized by its growth capacity at high temperature. Myriocin exposure also caused tolerance to soraphen A, an inhibitor of the acetyl‐CoA carboxylase Acc1, the rate‐limiting enzyme in fatty acid de novo production, supporting a change in lipid metabolism during ALE. In line with this, characterization of two randomly selected clones, LH03 and LH09, showed the presence of lipids with increased saturation degree and reduced acyl length. In addition, the clone LH03, which displays the greater improvement in fitness at 40°C, exhibited higher SL content as compared with the parental strain. Analysis of the LH03 and LH09 genomes revealed a loss of chromosomes affecting genes that have a role in fatty acid synthesis and elongation. The link between ploidy level and growth at high temperature was further supported by the analysis of a fully isogenic set of yeast strains with ploidy between 1N and 4N which showed that the loss of genome content provides heat tolerance. Consistent with this, a thermotolerant evolved population (LH40°) generated from the parental LH strain by heat‐driven ALE exhibited a reduction in the chromosome copy number. Thus, our results identify myriocin‐driven evolution as a powerful approach to investigate the mechanisms of acquired thermotolerance and to generate improved strains.

Link: doi.org/10.1111/1751-7915.13555

publications
cells, yeast, basic science
125
nature communications

Lipidomic and biophysical homeostasis of mammalian membranes counteracts dietary lipid perturbations to maintain cellular fitness

Kandice R Levental, Eric Malmberg, Jessica L Symons, Yang-Yi Fan, Robert S Chapkin, Robert Ernst, Ilya Levental

Proper membrane physiology requires maintenance of biophysical properties, which must be buffered from external perturbations. While homeostatic adaptation of membrane fluidity to temperature variation is a ubiquitous feature of ectothermic organisms, such responsive membrane adaptation to external inputs has not been directly observed in mammals. Here, we report that challenging mammalian membranes by dietary lipids leads to robust lipidomic remodeling to preserve membrane physical properties. Specifically, exogenous polyunsaturated fatty acids are rapidly incorporated into membrane lipids, inducing a reduction in membrane packing. These effects are rapidly compensated both in culture and in vivo by lipidome-wide remodeling, most notably upregulation of saturated lipids and cholesterol, resulting in recovery of membrane packing and permeability. Abrogation of this response results in cytotoxicity when membrane homeostasis is challenged by dietary lipids. These results reveal an essential mammalian mechanism for membrane homeostasis wherein lipidome remodeling in response to dietary lipid inputs preserves functional membrane phenotypes.

Link: doi.org/10.1038/s41467-020-15203-1

publications
other mammals, organelle, diet, basic science
126
Patent

Asparagine synthetase inhibitors and uses thereof

Alessandra Boletta, Christine Podrini, Isaline Rowe

The present invention relates to an inhibitor of asparagine synthase for use for the treatmentof a disorder characterized by renal and/or liver cyst formation and relative pharmaceutical composition. A comprehensive metabolomics characterisation of cells and renal tissues from a mouse model carrying the kidney-specific inactivation of the Pkdl gene was performed. Present data indicate a broad metabolic rewiring that involves several pathways including central carbon metabolism and glutamine utilisation. The inventors show that loss of Pkdl leads to profound metabolic changes that affect glycolysis, mitochondrial metabolism, and fatty acid synthesis (FAS). In particular, the inventors found that Pkdl-mutant cells preferentially use glutamine to fuel the TCA cycle, and to sustain FAS. Interfering with either glutamine uptake or FAS retards cell growth and survival. The inventors also found that the glutamine is diverted to asparagine via asparagine synthetase (ASNS). Notably, the silencing of ASNS was lethal in Pkdl-mutant cells when combined with glucose deprivation, opening novel therapeutic perspectives for ADPKD.

Link: freepatentsonline.com/WO2020049069A1.html

patents
mouse, cells, pharma
127
nature oncogene

The ACSL3-LPIAT1 signaling drives prostaglandin synthesis in non-small cell lung cancer

Maria Saliakoura, Inés Reynoso-Moreno, Chiara Pozzato, Matteo Rossi Sebastiano, Mirco Galié, Jürg Gertsch, Georgia Konstantinidou

Enhanced prostaglandin production promotes the development and progression of cancer. Prostaglandins are generated from arachidonic acid (AA) by the action of cyclooxygenase (COX) isoenzymes. However, how cancer cells are able to maintain an elevated supply of AA for prostaglandin production remains unclear. Here, by using lung cancer cell lines and clinically relevant KrasG12D-driven mouse models, we show that the long-chain acyl-CoA synthetase (ACSL3) channels AA into phosphatidylinositols to provide the lysophosphatidylinositol-acyltransferase 1 (LPIAT1) with a pool of AA to sustain high prostaglandin synthesis. LPIAT1 knockdown suppresses proliferation and anchorage-independent growth of lung cancer cell lines, and hinders in vivo tumorigenesis. In primary human lung tumors, the expression of LPIAT1 is elevated compared with healthy tissue, and predicts poor patient survival. This study uncovers the ACSL3-LPIAT1 axis as a requirement for the sustained prostaglandin synthesis in lung cancer with potential therapeutic value.

Link: doi.org/10.1038/s41388-020-1196-5

publications
human, cells, cancer
128
Applied and Environmental Microbiology

Yeast Viral Killer Toxin K1 Induces Specific Host Cell Adaptions via Intrinsic Selection Pressure

Stefanie Gier, Martin Simon, Gilles Gasparoni, Salem Khalifa, Marcel H Schulz, Manfred J Schmitt, Frank Breinig

The killer phenomenon in yeast (Saccharomyces cerevisiae) not only provides the opportunity to study host-virus interactions in a eukaryotic model but also represents a powerful tool to analyze potential coadaptional events and the role of killer yeast in biological diversity. Although undoubtedly having a crucial impact on the abundance and expression of the killer phenotype in killer-yeast harboring communities, the influence of a particular toxin on its producing host cell has not been addressed sufficiently. In this study, we describe a model system of two K1 killer yeast strains with distinct phenotypical differences pointing to substantial selection pressure in response to the toxin secretion level. Transcriptome and lipidome analyses revealed specific and intrinsic host cell adaptions dependent on the amount of K1 toxin produced. High basal expression of genes coding for osmoprotectants and stress-responsive proteins in a killer yeast strain secreting larger amounts of active K1 toxin implies a generally increased stress tolerance. Moreover, the data suggest that immunity of the host cell against its own toxin is essential for the balanced virus-host interplay providing valuable hints to elucidate the molecular mechanisms underlying K1 immunity and implicating an evolutionarily conserved role for toxin immunity in natural yeast populations.

The killer phenotype in Saccharomyces cerevisiae relies on the cytoplasmic persistence of two RNA viruses. In contrast to bacterial toxin producers, killer yeasts necessitate a specific immunity mechanism against their own toxin because they bear the same receptor populations as sensitive cells. Although the killer phenomenon is highly abundant and has a crucial impact on the structure of yeast communities, the influence of a particular toxin on its host cell has been barely addressed. In our study, we used two derivatives secreting different amount of the killer toxin K1 to analyze potential coadaptional events in this particular host/virus system. Our data underline the dependency of the host cell’s ability to cope with extracellular toxin molecules and intracellular K1 molecules provided by the virus. Therefore, this research significantly advances the current understanding of the evolutionarily conserved role of this molecular machinery as an intrinsic selection pressure in yeast populations.

Link: doi.org/10.1128/AEM.02446-19

publications
cells, yeast, basic science
129
Endocrine-Related Cancer

LDLR-mediated lipidome–transcriptome reprogramming in cisplatin insensitivity

Wei-Chun Chang, Hsiao-Ching Wang, Wei-Chung Cheng, Juan-Cheng Yang, Wei-Min Chung, Yen-Pin Ho, Lumin Chen, Yao-Ching Hung, Wen-Lung Ma

Platinum-based therapy remains the cornerstone for cancer therapy; however, its efficacy varies. The role of lipoprotein receptor-mediated lipid entry for cancer development has been reported. Yet, the roles and mechanism of the low-density lipoprotein receptor (LDLR) in chemo-sensitivities are unknown. In the current report, we used epithelial ovarian cancer (EOC), composed of various cellularities, to study this issue. Using public cDNA microarray database and single cohort study, LDLR expressions were positively associated with epithelial ovarian carcinomas (EOCs) platinum-based chemotherapy patients’ disease prognosis. In vitro and in vivo add-in/silencing LDLR was introduced to determine cisplatin sensitivity and cancer growth. Results revealed that knocked-down LDLR could sensitize while overexpressed LDLR could insensitize EOC cells to the cytotoxic effects of cisplatin. Moreover, the trans-omics approaches depicted an LDLR→LPC (Lyso-phosphatidylcholine)→FAM83B (phospholipase-related)→FGFRs (cisplatin sensitivity and phospholipase-related) regulatory axis. Finally, the manipulation of LDLR expression in EOC cells was found to determine the efficacy of cisplatin therapy in terms of tumor suppression. In conclusion, the LDLR→LPC→FAM83B→FGFRs axis is an example of tumor macroenvironmental regulation of therapy outcomes. Relatedly, LDLR expression could serve as a biomarker of chemotherapy sensitivity in EOCs. Significance: this study describes the role of LDLR in the development of insensitivity to platinum-based chemotherapy in epithelial ovarian cancer. The lipidome (e.g., LPC) and transcriptome (e.g., FAM38B) interactions revealed using trans-omics approaches an LDLR→LPC→FAM83B→FGFRs regulatory axis in cancer cells, in an animal model, and in patients.

Link: doi.org/10.1530/ERC-19-0095

publications
human, organ/tissue, mouse, cells, cancer
130
The FEBS Journal

Sex‐specific perturbation of complex lipids in response to medium‐chain fatty acids in very long‐chain acyl‐CoA dehydrogenase deficiency (VLCADD)

Khaled I Alatibi, Zeinab Wehbe, Ute Spiekerkoetter, Sara Tucci

Very‐long‐chain‐acyl‐CoA‐dehydrogenase‐deficiency (VLCAD) is the most common defect of long‐chain fatty acid β‐oxidation. The recommended treatment includes the application of medium‐chain‐triglycerides (MCT). However, long‐term treatment of VLCAD‐/‐ mice resulted in the development of a sex specific metabolic syndrome due to the selective activation of the ERK/mTORc1 signaling in females and ERK/PPARγ pathway in males.

In order to investigate a subsequent sex‐specific effect of MCT on the lipid composition of the cellular membranes, we performed lipidomic analysis, SILAC‐based quantitative proteomics and gene expression in fibroblasts from WT and VLCAD‐/‐ mice of both sexes.

Treatment with octanoate (C8) affected the composition of complex lipids resulting in a sex specific signature of the molecular profile. The content of ceramides and sphingomyelins in particular differed significantly under control conditions and increased markedly in cells from mutant female mice but remained unchanged in cells from mutant males. Moreover, we observed a specific upregulation of biosynthesis of plasmalogens only in male mice, whereas in females C8 led to the accumulation of higher concentration of phosphatidylcholines and lysophosphosphatidylcholines.

Our data on membrane lipids in VLCAD‐deficiency after supplementation with C8 provide evidence of a sex specific lipid perturbation. We hypothesize a likely C8‐induced pro‐inflammatory response contributing to the development of a severe metabolic syndrome in female VLCAD‐/‐ mice on long‐term MCT supplementation.

Link: doi.org/10.1111/febs.15221

publications
inflammation, mouse, cells, diet
131
Cell Reports

The Regulatory Proteins Rtg1/3 Govern Sphingolipid Homeostasis in the Human-Associated Yeast Candida albicans

Sergio D Moreno-Velásquez, Su Hlaing Tint, Valentina del Olmo Toledo, Sanda Torsin, Sonakshi De, J Christian Pérez

Integrating nutrient sensing with the synthesis of complex molecules is a central feature of metabolism. Yet the regulatory mechanisms underlying such integration are often unknown. Here, we establish that the transcription regulators Rtg1/3 are key determinants of sphingolipid homeostasis in the human fungal pathogen Candida albicans. Quantitative analysis of the C. albicans lipidome reveals Rtg1/3-dependent alterations in all complex sphingolipids and their precursors, ceramides. Mutations in the regulators render the fungus susceptible to myriocin, a sphingolipid synthesis inhibitor. Rtg1/3 exert control on the expression of several enzymes involved in the synthesis of sphingolipids’ building blocks, and the regulators are activated upon engulfment of C. albicans cells by human neutrophils. We demonstrate that Rtg1p and Rtg3p are regulated at two levels, one in response to sphingolipids and the other by the nutrient sensor TOR. Our findings, therefore, indicate that the Rtg1/3 system integrates nutrient sensing into the synthesis of complex lipids.

Link: doi.org/10.1016/j.celrep.2019.12.022

publications
cells, yeast, basic science
132
International Journal of Molecular Sciences

Association of α/β-Hydrolase D16B with Bovine Conception Rate and Sperm Plasma Membrane Lipid Composition

Shuwen Shan, Fangzheng Xu, Martina Bleyer, Svenja Becker, Torben Melbaum, Wilhelm Wemheuer, Marc Hirschfeld, Christin Wacker, Shuhong Zhao, Ekkehard Schütz, Bertram Brenig

We have identified a Holstein sire named Tarantino who had been approved for artificial insemination that is based on normal semen characteristics (i.e., morphology, thermoresistance, motility, sperm concentration), but had no progeny after 412 first inseminations, resulting in a non-return rate (NRdev) of −29. Using whole genome association analysis and next generation sequencing, an associated nonsense variant in the α/β-hydrolase domain-containing 16B gene (ABHD16B) on bovine chromosome 13 was identified. The frequency of the mutant allele in the German Holstein population was determined to be 0.0018 in 222,645 investigated cattle specimens. The mutant allele was traced back to Whirlhill Kingpin (bornFeb. 13th, 1959) as potential founder. The expression of ABHD16B was detected by Western blotting and immunohistochemistry in testis and epididymis of control bulls. A lipidome comparison of the plasma membrane of fresh semen from carriers and controls showed significant differences in the concentration of phosphatidylcholine (PC), diacylglycerol (DAG), ceramide (Cer), sphingomyelin (SM), and phosphatidylcholine (-ether) (PC O-), indicating that ABHD16B plays a role in lipid biosynthesis. The altered lipid contents may explain the reduced fertilization ability of mutated sperms.

Link: doi.org/10.3390/ijms21020627

publications
other mammals, agriculture, sperm
133
Cancer Research

Undermining glutaminolysis bolsters chemotherapy while NRF2 promotes chemoresistance in KRAS-driven pancreatic cancers

Suman Mukhopadhyay, Debanjan Goswami, Pavan P Adiseshaiah, William Burgan, Ming Yi, Theresa M Guerin, Serguei V Kozlov, Dwight V Nissley, Frank McCormick

Pancreatic cancer is a disease with limited therapeutic options. Resistance to chemotherapies poses a significant clinical challenge for pancreatic cancer patients and contributes to a high rate of recurrence. Here we showed that oncogenic KRAS, a critical driver of pancreatic cancer, promotes metabolic reprogramming and upregulates NRF2, a master regulator of the antioxidant network. NRF2 contributed to chemoresistance and was associated with a poor prognosis in pancreatic cancer patients. NRF2 activation metabolically rewired and elevated pathways involved in glutamine metabolism. This curbed chemoresistance in KRAS-mutant pancreatic cancers. Additionally, manipulating glutamine metabolism restrained the assembly of stress granules, an indicator of chemoresistance. Glutaminase inhibitors sensitized chemoresistant pancreatic cancer cells to gemcitabine, thereby improving the effectiveness of chemotherapy. This therapeutic approach holds promise as a novel therapy for pancreatic cancer patients harboring KRAS mutation.

Link: doi.org/10.1158/0008-5472.CAN-19-1363

publications
human, cells, cancer
134
British Journal of Pharmacology

Preclinical pharmacological evaluation of the fatty acid amide hydrolase inhibitor BIA 10‐2474

Maria‐João Bonifácio, Filipa Sousa, Cátia Aires, Ana Loureiro, Carlos Fernandes‐Lopes, Nuno Pires, P Nuno Palma, Paul Moser, Patrício Soares‐da‐Silva

In 2016 one person died and four others had mild‐to‐severe neurological symptoms during a phase I clinical trial of the FAAH inhibitor BIA 10‐2474.

Pharmacodynamic and pharmacokinetic studies were performed with BIA 10‐2474 in comparison with PF‐04457845 and JNJ‐42165279 using mice, rats and human FAAH expressed in COS cells. Selectivity was evaluated by APBB in rat. BIA 10‐2474 effect in stroke‐prone spontaneously hypertensive rats (SHRSP) was explored.

BIA 10‐2474 was about 10‐fold less potent than PF‐04457845 in inhibiting human FAAH in situ, but inhibited mouse brain and liver FAAH with ED50 values of 13.5 and 6.2 μg.kg‐1, respectively. Plasma and brain BIA 10‐2474 levels were consistent with in situ potency and neither BIA 10‐2474 nor its metabolites accumulated following repeat administration. FAAH and ABHD6 were identified as primary targets of BIA 10‐2474 and, at higher exposure levels, ABHD11, PNPLA6, PLA2G15, PLA2G6 and AIG1. At 100 mg.kg‐1 for 28 days the level of several lipid species containing arachidonic acid increased. Daily treatment of SHRSP with BIA 10‐2474 did not affect mortality rate and, in surviving animals, did not increase the incidence of haemorrhage or oedema.

BIA 10‐2474 potently inhibits FAAH in vivo, similarly to PF‐04457845, but also interacts with a number of lipid processing enzymes, some previously identified in human cells as off‐targets particularly at high levels of exposure. These interactions occurred at doses used in toxicology studies, but the implication of these off‐targets in the clinical trial accident remains unclear.

Link: doi.org/10.1111/bph.14973

publications
organ/tissue, clinical, other mammals, pharma, neuro
135
Patent

MicroRNA Targeting Agent for Treatment of Heart Disease

Jaya Krishnan, Corinne Bischof

The present invention relates to the treatment and prevention of heart disease by administering oligonucleic acid agents that modulate the activity or expression of microRNAs. More precisely, the invention provides methods for treating or preventing heart disease by inhibiting the expression and/or activity of the microRNA miR27b-5p.

Link: freepatentsonline.com/WO2020002694A1.html

patents
organ/tissue, mouse, cvd
136
Diabetes Care

Plasma Lipidome and Prediction of Type 2 Diabetes in the Population-Based Malmö Diet and Cancer Cohort

Céline Fernandez, Michal A Surma, Christian Klose, Mathias J Gerl, Filip Ottosson, Ulrika Ericson, Nikolay Oskolkov, Marju Ohro-Melander, Kai Simons, Olle Melander

Type 2 diabetes mellitus (T2DM) is associated with dyslipidemia, but the detailed alterations in lipid species preceding the disease are largely unknown. We aimed to identify plasma lipids associated with development of T2DM and investigate their associations with lifestyle.

178 lipids were measured at baseline by mass spectrometry in 3,668 participants without diabetes from the Malmö Diet and Cancer Study. The population was randomly split into discovery (n = 1,868, including 257 incident cases) and replication (n = 1,800, including 249 incident cases) sets. We used orthogonal projections to latent structures discriminant analyses, extracted a predictive component for T2DM incidence (lipid-PCDM), and assessed its association with T2DM incidence using Cox regression and lifestyle factors using general linear models.

A T2DM-predictive lipid-PCDM derived from the discovery set was independently associated with T2DM incidence in the replication set, with hazard ratio (HR) among subjects in the fifth versus first quintile of lipid-PCDM of 3.7 (95% CI 2.2–6.5). In comparison, the HR of T2DM among obese versus normal weight was 1.8 (95% CI 1.2–2.6). Clinical lipids did not improve T2DM risk prediction, but adding the lipid-PCDM to all conventional T2DM risk factors increased the area under the receiver operating characteristics curve by 3%. The lipid-PCDM was also associated with a dietary risk score for T2DM incidence and lower level of physical activity.

A lifestyle-related lipidomic profile strongly predicts T2DM development beyond current risk factors. Further studies are warranted to test if lifestyle interventions modifying this lipidomic profile can prevent T2DM.

Link: doi.org/10.2337/dc19-1199

publications
human, plasma/serum, clinical, biomarker, diabetes, obesity
137
Cell Reports

Suppressing Aneuploidy-Associated Phenotypes Improves the Fitness of Trisomy 21 Cells

Sunyoung Hwang, Jessica F Williams, Maja Kneissig, Maria Lioudyno, Isabel Rivera, Pablo Helguera, Jorge Busciglio, Zuzana Storchova, Megan C King, Eduardo M Torres

An abnormal number of chromosomes, or aneuploidy, accounts for most spontaneous abortions, causes developmental defects, and is associated with aging and cancer. The molecular mechanisms by which aneuploidy disrupts cellular function remain largely unknown. Here, we show that aneuploidy disrupts the morphology of the nucleus. Mutations that increase the levels of long-chain bases suppress nuclear abnormalities of aneuploid yeast independent of karyotype identity. Quantitative lipidomics indicates that long-chain bases are integral components of the nuclear membrane in yeast. Cells isolated from patients with Down syndrome also show that abnormal nuclear morphologies and increases in long-chain bases not only suppress these abnormalities but also improve their fitness. We obtained similar results with cells isolated from patients with Patau or Edward syndrome, indicating that increases in long-chain bases improve the fitness of aneuploid cells in yeast and humans. Targeting lipid biosynthesis pathways represents an important strategy to suppress nuclear abnormalities in aneuploidy-associated diseases.

Link: doi.org/10.1016/j.celrep.2019.10.059

publications
organelle, yeast, basic science
138
The Journal of Clinical Endocrinology & Metabolism

Shotgun lipidomics discovered diurnal regulation of lipid metabolism linked to insulin sensitivity in non-diabetic men

Katharina Kessler, Mathias J Gerl, Silke Hornemann, Markus Damm, Christian Klose, Klaus J Petzke, Margrit Kemper, Daniela Weber, Natalia Rudovich, Tilman Grune, Kai Simons, Achim Kramer, Andreas F H Pfeiffer, Olga Pivovarova-Ramich

Meal timing affects metabolic homeostasis and body weight, but how composition and timing of meals affect plasma lipidomics in humans is not well studied.

We used high throughput shotgun plasma lipidomics to investigate effects of timing of carbohydrate and fat intake on lipid metabolism and its relation to glycaemic control.

29 non-diabetic men consumed (i) a high-carb test meal (MTT-HC) at 09:00 and a high-fat meal (MTT-HF) at 15:40; or (ii) MTT-HF at 09:00 and MTT-HC at 15:40. Blood was sampled before and 180 min after completion of each MTT. Subcutaneous adipose tissue (SAT) was collected after overnight fast and both MTTs. Prior to each investigation day, participants consumed a 4-week isocaloric diet of the same composition: (1) high-carb meals until 13:30 and high-fat meals between 16:30 and 22:00 or (2) the inverse order.

12h-daily lipid patterns showed a complex regulation by both the time of day (67.8%) and meal composition (55.4%). A third of lipids showed a diurnal variation in postprandial responses to the same meal with mostly higher responses in the morning than in the afternoon. Triacylglycerols containing shorter and more saturated fatty acids were enriched in the morning. SAT transcripts involved in fatty acid synthesis and desaturation showed no diurnal variation. Diurnal changes of seven lipid classes were negatively associated with insulin sensitivity, but not with glucose and insulin response or insulin secretion.

This study identified postprandial plasma lipid profiles as being strongly affected by meal timing and associated with insulin sensitivity.

Link: doi.org/10.1210/clinem/dgz176

publications
human, organ/tissue, plasma/serum, clinical, diet, diabetes
139
BBA Molecular and Cell Biology of Lipids

Pho85 and PI(4,5)P2 regulate different lipid metabolic pathways in response to cold

Jose A Prieto, Francisco Estruch, Isaac Córcoles-Sáez, Maurizio Del Poeta, Robert Rieger, Irene Stenzel, Francisca Randez-Gil

Lipid homeostasis allows cells to adjust membrane biophysical properties in response to changes in environmental conditions. In the yeast Saccharomyces cerevisiae, a downward shift in temperature from an optimal reduces membrane fluidity, which triggers a lipid remodeling of the plasma membrane. How changes in membrane fluidity are perceived, and how the abundance and composition of different lipid classes is properly balanced, remain largely unknown. Here, we show that the levels of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], the most abundant plasma membrane phosphoinositide, drop rapidly in response to a downward shift in temperature. This change triggers a signaling cascade transmitted to cytosolic diphosphoinositol phosphate derivatives, among them 5-PP-IP4 and 1-IP7, that exert regulatory functions on genes involved in the inositol and phospholipids (PLs) metabolism, and inhibit the activity of the protein kinase Pho85. Consistent with this, cold exposure triggers a specific program of neutral lipids and PLs changes. Furthermore, we identified Pho85 as playing a key role in controlling the synthesis of long-chain bases (LCBs) via the Ypk1-Orm2 regulatory circuit. We conclude that Pho85 orchestrates a coordinated response of lipid metabolic pathways that ensure yeast thermal adaptation.

Link: doi.org/10.1016/j.bbalip.2019.158557

publications
cells, yeast, basic science
140
PLOS Biology

Machine learning of human plasma lipidomes for obesity estimation in a large population cohort

Mathias J Gerl, Christian Klose, Michal A Surma, Céline Fernandez, Olle Melander, Satu Männistö, Katja Borodulin, Aki S Havulinna, Veikko Salomaa, Elina Ikonen, Carlo V Cannistraci, Kai Simons

Obesity is associated with changes in the plasma lipids. Although simple lipid quantification is routinely used, plasma lipids are rarely investigated at the level of individual molecules. We aimed at predicting different measures of obesity based on the plasma lipidome in a large population cohort using advanced machine learning modeling. A total of 1,061 participants of the FINRISK 2012 population cohort were randomly chosen, and the levels of 183 plasma lipid species were measured in a novel mass spectrometric shotgun approach. Multiple machine intelligence models were trained to predict obesity estimates, i.e., body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR), and body fat percentage (BFP), and validated in 250 randomly chosen participants of the Malmö Diet and Cancer Cardiovascular Cohort (MDC-CC). Comparison of the different models revealed that the lipidome predicted BFP the best (R2=0.73), based on a Lasso model. In this model, the strongest positive and the strongest negative predictor were sphingomyelin molecules, which differ by only 1 double bond, implying the involvement of an unknown desaturase in obesity-related aberrations of lipid metabolism. Moreover, we used this regression to probe the clinically relevant information contained in the plasma lipidome and found that the plasma lipidome also contains information about body fat distribution, because WHR (R2=0.65) was predicted more accurately than BMI (R2=0.47). These modeling results required full resolution of the lipidome to lipid species level, and the predicting set of biomarkers had to be sufficiently large. The power of the lipidomics association was demonstrated by the finding that the addition of routine clinical laboratory variables, e.g., high-density lipoprotein (HDL)- or low-density lipoprotein (LDL)- cholesterol did not improve the model further. Correlation analyses of the individual lipid species, controlled for age and separated by sex, underscores the multiparametric and lipid species-specific nature of the correlation with the BFP. Lipidomic measurements in combination with machine intelligence modeling contain rich information about body fat amount and distribution beyond traditional clinical assays.

Link: doi.org/10.1371/journal.pbio.3000443

publications
human, plasma/serum, clinical, biomarker, obesity
141
Clinical Nutrition

Impact of multi-micronutrient supplementation on lipidemia of children and adolescents

Anirikh Chakrabarti, Michael Eiden, Delphine Morin-Rivron, Nicolas Christinat, Jacqueline P Monteiro, Jim Kaput, Mojgan Masoodi

Micronutrient supplementation has been extensively explored as a strategy to improve health and reduce risk of chronic diseases. Fat-soluble vitamins like A and E with their antioxidant properties and mechanistic interactions with lipoproteins, have potentially a key impact on lipid metabolism and lipidemia. The impact of micronutrients on lipid metabolism requires further investigation including characterization of plasma lipidome following supplementation and any cause-effect on circulating lipids. In this study, we elucidate the effect and associations of a multi-micronutrient intervention in Brazilian children and teens with lipoprotein alterations and lipid metabolism. Our analysis suggests a combination of short and long-term impact of supplementation on lipid metabolism, potentially mediated primarily by α-tocopherol (vitamin E) and retinol (vitamin A). Among the lipid classes, levels of phospholipids, lysophospholipids, and cholesterol esters were impacted the most along with differential incorporation of stearic, palmitic, oleic and arachidonic acids. Integrated analysis with proteomic data suggested potential links to supplementation-mediated alterations in protein levels of phospholipases and pyruvate dehydrogenase kinase 1 (PDK1). Associations between the observed differences in lipidemia, total triglyceride, and VLDL-cholesterol levels suggest that micronutrients may play a role in reducing these risk factors for cardiovascular disease in children. This would require further investigation.

Link: doi.org/10.1016/j.clnu.2019.09.010

publications
human, plasma/serum, clinical, diet
142
Frontiers in Cell and Developmental Biology

Role of Neutral Sphingomyelinase-2 (NSM 2) in the Control of T Cell Plasma Membrane Lipid Composition and Cholesterol Homeostasis

Charlene Börtlein, Fabian Schumacher, Burkhard Kleuser, Lars Dölken, Elita Avota

The activity of neutral sphingomyelinase-2 (NSM2) to catalyze the conversion of sphingomyelin (SM) to ceramide and phosphocholine at the cytosolic leaflet of plasma membrane (PM) is important in T cell receptor (TCR) signaling. We recently identified PKCζ as a major NSM2 downstream effector which regulates microtubular polarization. It remained, however, unclear to what extent NSM2 activity affected overall composition of PM lipids and downstream effector lipids in antigen stimulated T cells. Here, we provide a detailed lipidomics analyses on PM fractions isolated from TCR stimulated wild type and NSM2 deficient (ΔNSM) Jurkat T cells. This revealed that in addition to that of sphingolipids, NSM2 depletion also affected concentrations of many other lipids. In particular, NSM2 ablation resulted in increase of lyso-phosphatidylcholine (LPC) and lyso-phosphatidylethanolamine (LPE) which both govern PM biophysical properties. Crucially, TCR dependent upregulation of the important T cell signaling lipid diacylglycerol (DAG), which is fundamental for activation of conventional and novel PKCs, was abolished in ΔNSM cells. Moreover, NSM2 activity was found to play an important role in PM cholesterol transport to the endoplasmic reticulum (ER) and production of cholesteryl esters (CE) there. Most importantly, CE accumulation was essential to sustain human T cell proliferation. Accordingly, inhibition of CE generating enzymes, the cholesterol acetyltransferases ACAT1/SOAT1 and ACAT2/SOAT2, impaired TCR driven expansion of both CD4+ and CD8+ T cells. In summary, our study reveals an important role of NSM2 in regulating T cell functions by its multiple effects on PM lipids and cholesterol homeostasis.

Link: doi.org/10.3389/fcell.2019.00226

publications
human, organelle, immuno
143
nature communications

Genetic architecture of human plasma lipidome and its link to cardiovascular disease

Rubina Tabassum, Joel T Rämö, Pietari Ripatti, Jukka T Koskela, Mitja Kurki, Juha Karjalainen, Priit Palta, Shabbeer Hassan, Javier Nunez-Fontarnau, Tuomo T J Kiiskinen, Sanni Söderlund, Niina Matikainen, Mathias J Gerl, Michal A Surma, Christian Klose, Nathan O Stitziel, Hannele Laivuori, Aki S Havulinna, Susan K Service, Veikko Salomaa, Matti Pirinen, Matti Jauhiainen, Mark J Daly, Nelson B Freimer, Aarno Palotie, Marja-Riitta Taskinen, Kai Simons, Samuli Ripatti

Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.

Link: doi.org/10.1038/s41467-019-11954-8

publications
human, plasma/serum, clinical, biomarker, cvd
144
Kidney international

Integrative analysis of prognostic biomarkers derived from multiomics panels helps discrimination of chronic kidney disease trajectories in people with type 2 diabetes

Michael Kammer, Andreas Heinzel, Jill A Willency, Kevin L Duffin, Gert Mayer, Kai Simons, Mathias J Gerl, Christian Klose, Georg Heinze, Roman Reindl-Schwaighofer, Karin Hu, Paul Perco, Susanne Eder, Laszlo Rosivall, Patrick B Mark, Wenjun Ju, Matthias Kretzler, Mark I McCarthy, Hiddo L Heerspink, Andrzej Wiecek, Maria F Gomez, Rainer Oberbauer

Clinical risk factors explain only a fraction of the variability of estimated glomerular filtration rate (eGFR) decline in people with type 2 diabetes. Cross-omics technologies by virtue of; a wide spectrum screening of plasma samples have the potential to identify biomarkers for the refinement of prognosis in addition to clinical variables. Here we utilized proteomics, metabolomics and lipidomics panel assay measurements in baseline plasma samples from the multinational PROVALID study (PROspective cohort study in patients with type 2 diabetes mellitus for VALIDation of biomarkers) of patients with incident or early chronic kidney disease (median follow-up 35 months, median baseline eGFR 84 mL/min/1.73m2, urine albumin-to-creatinine ratio 8.1 mg/g). In an accelerated case-control study, 258 individuals with a stable eGFR course (median eGFR change 0.1 mL/min/year) were compared to 223 individuals with a rapid eGFR decline (median eGFR decline -6.75 mL/min/year) using Bayesian multivariable logistic regression models to assess the discrimination of eGFR trajectories. The analysis included 402 candidate predictors and showed two protein markers (KIM-1, NTproBNP) to be relevant predictors of the eGFR trajectory with baseline eGFR being an important clinical covariate. The inclusion of metabolomic and lipidomic platforms did not improve discrimination substantially. Predictions using all available variables were statistically indistinguishable from predictions using only KIM-1 and baseline eGFR (area under the receiver operating characteristic curve 0.63). Thus, the discrimination of eGFR trajectories in patients with incident or early diabetic kidney disease and maintained baseline eGFR was modest and the protein marker KIM-1 was the most important predictor.

Link: doi.org/10.1016/j.kint.2019.07.025

publications
human, plasma/serum, clinical, biomarker, diabetes
145
Molecular Cell

Osh Proteins Control Nanoscale Lipid Organization Necessary for PI(4,5)P2 Synthesis

Taki Nishimura, Michael Gecht, Roberto Covino, Gerhard Hummer, Michal A Surma, Christian Klose, Hiroyuki Arai, Nozomu Kono, Christopher J Stefan

The plasma membrane (PM) is composed of a complex lipid mixture that forms heterogeneous membrane environments. Yet, how small-scale lipid organization controls physiological events at the PM remains largely unknown. Here, we show that ORP-related Osh lipid exchange proteins are critical for the synthesis of phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P2], a key regulator of dynamic events at the PM. In real-time assays, we find that unsaturated phosphatidylserine (PS) and sterols, both Osh protein ligands, synergistically stimulate phosphatidylinositol 4-phosphate 5-kinase (PIP5K) activity. Biophysical FRET analyses suggest an unconventional co-distribution of unsaturated PS and phosphatidylinositol 4-phosphate (PI4P) species in sterol-containing membrane bilayers. Moreover, using in vivo imaging approaches and molecular dynamics simulations, we show that Osh protein-mediated unsaturated PI4P and PS membrane lipid organization is sensed by the PIP5K specificity loop. Thus, ORP family members create a nanoscale membrane lipid environment that drives PIP5K activity and PI(4,5)P2 synthesis that ultimately controls global PM organization and dynamics.

Link: doi.org/10.1016/j.molcel.2019.06.037

publications
cells, yeast, basic science
146
Journal of Cell Biology

Lipid droplet size directs lipolysis and lipophagy catabolism in hepatocytes

Micah B Schott, Shaun G Weller, Ryan J Schulze, Eugene W Krueger, Kristina Drizyte-Miller, Carol A Casey, Mark A McNiven

Lipid droplet (LD) catabolism in hepatocytes is mediated by a combination of lipolysis and a selective autophagic mechanism called lipophagy, but the relative contributions of these seemingly distinct pathways remain unclear. We find that inhibition of lipolysis, lipophagy, or both resulted in similar overall LD content but dramatic differences in LD morphology. Inhibition of the lipolysis enzyme adipose triglyceride lipase (ATGL) resulted in large cytoplasmic LDs, whereas lysosomal inhibition caused the accumulation of numerous small LDs within the cytoplasm and degradative acidic vesicles. Combined inhibition of ATGL and LAL resulted in large LDs, suggesting that lipolysis targets these LDs upstream of lipophagy. Consistent with this, ATGL was enriched in larger-sized LDs, whereas lipophagic vesicles were restricted to small LDs as revealed by immunofluorescence, electron microscopy, and Western blot of size-separated LDs. These findings provide new evidence indicating a synergistic relationship whereby lipolysis targets larger-sized LDs to produce both size-reduced and nascently synthesized small LDs that are amenable for lipophagic internalization.

Link: doi.org/10.1083/jcb.201803153

publications
other mammals, cells, basic science
147
Molecular Metabolism

Multi-omics insights into functional alterations of the liver in insulin-deficient diabetes mellitus

Mattias Backman, Florian Flenkenthaler, Andreas Blutke, Maik Dahlhoff, Erik Ländström, Simone Renner, Julia Philippou-Massier, Stefan Krebs, Birgit Rathkolb, Cornelia Prehn, Michal Grzybek, Ünal Coskun, Michael Rothe, Jerzy Adamski, Martin Hrabe de Angelis, Rüdiger Wanke, Thomas Fröhlich, Georg J Arnold, Helmut Blum, Eckhard Wolf

The liver regulates the availability of insulin to other tissues and is the first line insulin response organ physiologically exposed to higher insulin concentrations than the periphery. Basal insulin during fasting inhibits hepatic gluconeogenesis and glycogenolysis, whereas postprandial insulin peaks stimulate glycogen synthesis. The molecular consequences of chronic insulin deficiency for the liver have not been studied systematically.

We analyzed liver samples of a genetically diabetic pig model (MIDY) and of wild-type (WT) littermate controls by RNA sequencing, proteomics, and targeted metabolomics/lipidomics.

Cross-omics analyses revealed increased activities in amino acid metabolism, oxidation of fatty acids, ketogenesis, and gluconeogenesis in the MIDY samples. In particular, the concentrations of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) and of retinol dehydrogenase 16 (RDH16), which catalyzes the first step in retinoic acid biogenesis, were highly increased. Accordingly, elevated levels of retinoic acid, which stimulates the expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PCK1), were measured in the MIDY samples. In contrast, pathways related to extracellular matrix and inflammation/pathogen defense response were less active than in the WT samples.

The first multi-omics study of a clinically relevant diabetic large animal model revealed molecular signatures and key drivers of functional alterations of the liver in insulin-deficient diabetes mellitus. The multi-omics data set provides a valuable resource for comparative analyses with other experimental or clinical data sets.

Link: doi.org/10.1016/j.molmet.2019.05.011

publications
organ/tissue, clinical, other mammals, biomarker, diabetes
148
BBA Molecular and Cell Biology of Lipids

The emerging role of the mitochondrial fatty-acid synthase (mtFASII) in the regulation of energy metabolism

Zeinab Wehbe, Sidney Behringer, Khaled Alatibi, David Watkins, David Rosenblatt, Ute Spiekerkoetter, Sara Tucci

Malonyl-CoA synthetase (ACSF3) catalyzes the first step of the mitochondrial fatty acid biosynthesis (mtFASII). Mutations in ACSF3 cause CMAMMA a rare inborn error of metabolism. The clinical phenotype is very heterogeneous, with some patients presenting with neurologic manifestations. In some children, presenting symptoms such as coma, ketoacidosis and hypoglycemia are suggestive of an intermediary metabolic disorder. The overall pathophysiological mechanisms are not understood.

In order to study the role of mtFASII in the regulation of energy metabolism we performed a comprehensive metabolic phenotyping with Seahorse technology proteomics in fibroblasts from healthy controls and ACSF3 patients. SILAC-based proteomics and lipidomic analysis were performed to investigate the effects of hypofunctional mtFASII on proteome and lipid homeostasis of complex lipids.

Our data clearly confirmed an impaired mitochondrial flexibility characterized by reduced mitochondrial respiration and glycolytic flux due to a lower lipoylation degree. These findings were accompanied by the adaptational upregulation of β-oxidation and by the reduction of anaplerotic amino acids as compensatory mechanism to address the required energy need. Finally, lipidomic analysis demonstrated that the content of the bioactive lipids sphingomyelins and cardiolipins was strongly increased.

Our data clearly demonstrate the role of mtFASII in metabolic regulation. Moreover, we show that mtFASII acts as mediator in the lipid-mediated signaling processes in the regulation of energy homeostasis and metabolic flexibility.

Link: doi.org/10.1016/j.bbalip.2019.07.012

publications
human, cells, basic science
149
Journal of the AHA

Coronary Artery Disease Risk and Lipidomic Profiles Are Similar in Hyperlipidemias With Family History and Population‐Ascertained Hyperlipidemias

Joel T Rämö, Pietari Ripatti, Rubina Tabassum, Sanni Söderlund, Nina Matikainen, Mathias J Gerl, Christian Klose, Michal A Surma, Nathan O Stitziel, Aki S Havulinna, Matti Pirinen, Veikko Salomaa, Nelson B Freimer, Matti Jauhiainen, Aarno Palotie, Marja-Riitta Taskinen, Kai Simons, Samuli Ripatti

We asked whether, after excluding familial hypercholesterolemia, individuals with high low‐density lipoprotein cholesterol (LDL‐C) or triacylglyceride levels and a family history of the same hyperlipidemia have greater coronary artery disease risk or different lipidomic profiles compared with population‐based hyperlipidemias.

We determined incident coronary artery disease risk for 755 members of 66 hyperlipidemic families (≥2 first‐degree relatives with similar hyperlipidemia) and 19 644 Finnish FINRISK population study participants. We quantified 151 circulating lipid species from 550 members of 73 hyperlipidemic families and 897 FINRISK participants using mass spectrometric shotgun lipidomics. Familial hypercholesterolemia was excluded using functional LDL receptor testing and genotyping. Hyperlipidemias (LDL‐C or triacylglycerides >90th population percentile) associated with increased coronary artery disease risk in meta‐analysis of the hyperlipidemic families and the population cohort (high LDL‐C: hazard ratio, 1.74 [95% CI, 1.48–2.04]; high triacylglycerides: hazard ratio, 1.38 [95% CI, 1.09–1.74]). Risk estimates were similar in the family and population cohorts also after adjusting for lipid‐lowering medication. In lipidomic profiling, high LDL‐C associated with 108 lipid species, and high triacylglycerides associated with 131 lipid species in either cohort (at 5% false discovery rate; P‐value range 0.038–2.3×10−56). Lipidomic profiles were highly similar for hyperlipidemic individuals in the families and the population (LDL‐C: r=0.80; triacylglycerides: r=0.96; no lipid species deviated between the cohorts).

Hyperlipidemias with family history conferred similar coronary artery disease risk as population‐based hyperlipidemias. We identified distinct lipidomic profiles associated with high LDL‐C and triacylglycerides. Lipidomic profiles were similar between hyperlipidemias with family history and population‐ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms.

Link: doi.org/10.1161/JAHA.119.012415

publications
human, plasma/serum, clinical, cvd
150
Patent

Means and methods to treat dystonia

Rose E Goodchild, Micheline Grillet

The present application relates to the field of neurological diseases, particularly to dystonia, even more particularly to primary dystonia, most particularly DYT1 primary dystonia. It is disclosed that the DYT1 dystonia causative mutation in TORSIN1A leads to hyperactivation of LIPIN. The invention provides substances modulating LIPIN function, in particular RNA molecules inhibiting LIPIN function and medical uses of these LIPIN inhibitors. Methods are disclosed to screen for medicaments that counteract the effects of TORSIN1A mutation.

Link: freepatentsonline.com/y2019/0160184.html

patents
cells, pharma, insects, neuro, method
151
Cell

CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondrial Fragmentation in Obesity

Philipp Hammerschmidt, Daniela Ostkotte, Hendrik Nolte, Mathias J Gerl, Alexander Jais, Hanna L Brunner, Hans-Georg Sprenger, Motoharu Awazawa, Hayley T Nicholls, Sarah M Turpin-Nolan, Thomas Langer, Marcus Krüger, Britta Brügger, Jens C Brüning

Ectopic lipid deposition and altered mitochondrial dynamics contribute to the development of obesity and insulin resistance. However, the mechanistic link between these processes remained unclear. Here we demonstrate that the C 16:0 sphingolipid synthesizing ceramide synthases, CerS5 and CerS6, affect distinct sphingolipid pools and that abrogation of CerS6 but not of CerS5 protects from obesity and insulin resistance. We identify proteins that specifically interact with C 16:0 sphingolipids derived from CerS5 or CerS6. Here, only CerS6-derived C 16:0 sphingolipids bind the mitochondrial fission factor (Mff). CerS6 and Mff deficiency protect from fatty acid-induced mitochondrial fragmentation in vitro, and the two proteins genetically interact in vivo in obesity-induced mitochondrial fragmentation and development of insulin resistance. Our experiments reveal an unprecedented specificity of sphingolipid signaling depending on specific synthesizing enzymes, provide a mechanistic link between hepatic lipid deposition and mitochondrial fragmentation in obesity, and define the CerS6-derived sphingolipid/Mff interaction as a therapeutic target for metabolic diseases.

Link: doi.org/10.1016/j.cell.2019.05.008

publications
human, mouse, cells, diabetes, obesity
152
Molecular Metabolism

Comprehensive and quantitative analysis of white and brown adipose tissue by shotgun lipidomics

Michal Grzybek, Alessandra Palladini, Vasileia I Alexaki, Michal A Surma, Kai Simons, Triantafyllos Chavakis, Christian Klose, Ünal Coskun

Shotgun lipidomics enables an extensive analysis of lipids from tissues and fluids. Each specimen requires appropriate extraction and processing procedures to ensure good coverage and reproducible quantification of the lipidome. Adipose tissue (AT) has become a research focus with regard to its involvement in obesity-related pathologies. However, the quantification of the AT lipidome is particularly challenging due to the predominance of triacylglycerides, which elicit high ion suppression of the remaining lipid classes.

We present a new and validated method for shotgun lipidomics of AT, which tailors the lipid extraction procedure to the target specimen and features high reproducibility with a linear dynamic range of at least 4 orders of magnitude for all lipid classes. Utilizing this method, we observed tissue-specific and diet-related differences in three AT types (brown, gonadal, inguinal subcutaneous) from lean and obese mice. Brown AT exhibited a distinct lipidomic profile with the greatest lipid class diversity and responded to high-fat diet by altering its lipid composition, which shifted towards that of white AT. Moreover, diet-induced obesity promoted an overall remodelling of the lipidome, where all three AT types featured a significant increase in longer and more unsaturated triacylglyceride and phospholipid species.

The here presented method facilitates reproducible systematic lipidomic profiling of AT and could be integrated with further –omics approaches used in (pre-) clinical research, in order to advance the understanding of the molecular metabolic dynamics involved in the pathogenesis of obesity-associated disorders.

Link: doi.org/10.1016/j.molmet.2019.01.009

publications
organ/tissue, mouse, clinical, biomarker, diet, obesity, method
153
BBA Biomembranes

Membrane cholesterol depletion reduces downstream signaling activity of the adenosine A2a receptor

Claire McGraw, Lewen Yang, Ilya Levental, Edward Lyman, Anne Skaja-Robinson

Cholesterol has been shown to modulate the activity of multiple G Protein-coupled receptors (GPCRs), yet whether cholesterol acts through specific interactions, indirectly via modifications to the membrane, or via both mechanisms is not well understood. High-resolution crystal structures of GPCRs have identified bound cholesterols; based on a β2-adrenergic receptor (β2AR) structure bound to cholesterol and the presence of conserved amino acids in class A receptors, the cholesterol consensus motif (CCM) was identified. Here in mammalian cells expressing A2aR, ligand dependent production of cAMP is reduced following membrane cholesterol depletion with methyl-beta-cyclodextrin (MβCD), indicating that adenosine A2a receptor (A2aR) signaling is dependent on cholesterol. In contrast, ligand binding is not dependent on cholesterol depletion. All-atom molecular simulations suggest that cholesterol interacts specifically with the CCM when the receptor is in an active state, but not when in an inactive state. Taken together, the data support a model of receptor state-dependent binding between cholesterol and the CCM, which could facilitate both G-protein coupling and downstream signaling of A2aR.

Link: doi.org/10.1016/j.bbamem.2019.01.001

publications
human, organelle, basic science
154
Nature Communications Biology

Dissection of metabolic reprogramming in polycystic kidney disease reveals coordinated rewiring of bioenergetic pathways

Christine Podrini, Isaline Rowe, Roberto Pagliarini, Ana S H Costa, Marco Chiaravalli, Ivano Di Meo, Hyunho Kim, Gianfranco Distefano, Valeria Tiranti, Feng Qian, Diego di Bernardo, Christian Frezza, Alessandra Boletta

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder caused by loss-of-function mutations in PKD1 or PKD2. Increased glycolysis is a prominent feature of the disease, but how it impacts on other metabolic pathways is unknown. Here, we present an analysis of mouse Pkd1 mutant cells and kidneys to investigate the metabolic reprogramming of this pathology. We show that loss of Pkd1 leads to profound metabolic changes that affect glycolysis, mitochondrial metabolism, and fatty acid synthesis (FAS). We find that Pkd1-mutant cells preferentially use glutamine to fuel the TCA cycle and to sustain FAS. Interfering with either glutamine uptake or FAS retards cell growth and survival. We also find that glutamine is diverted to asparagine via asparagine synthetase (ASNS). Transcriptional profiling of PKD1-mutant human kidneys confirmed these alterations. We find that silencing of Asns is lethal in Pkd1-mutant cells when combined with glucose deprivation, suggesting therapeutic approaches for ADPKD.

Link: doi.org/10.1038/s42003-018-0200-x

publications
organ/tissue, mouse, basic science
155
Patent

Compositions for facilitating membrane fusion and uses thereof

Geoffrey A Von Maltzahn, John M Milwid, Michael T Mee, Jacob Rosenblum-Rubens, Nathan Wilson-Stebbins, Molly K Gibson, Neal F Gordon, Bo Zhang, Kyle M Trudeau, Brigham J Hartley, Tamar R Putiri, Kiana Mahdaviani, Matthew Milnes-Dobbin

In some aspects, fusosome compositions and methods are described herein that comprise membrane enclosed preparations, comprising a fusogen. In some embodiments, the fusosome can target the cell, thereby delivering complex biologic agents to the target cell cytoplasm.

Link: freepatentsonline.com/WO2018208728A1.html

patents
organelle, pharma, method
156
Science

Viscous control of cellular respiration by membrane lipid composition

Itay Budin, Tristan de Rond, Yan Chen, Leanne J G Chan, Christopher J Petzold, Jay D Keasling

Lipid composition determines the physical properties of biological membranes and can vary substantially between and within organisms. We describe a specific role for the viscosity of energy-transducing membranes in cellular respiration. Engineering of fatty acid biosynthesis in Escherichia coli allowed us to titrate inner membrane viscosity across a 10-fold range by controlling the abundance of unsaturated or branched lipids. These fluidizing lipids tightly controlled respiratory metabolism, an effect that can be explained with a quantitative model of the Electron Transport Chain (ETC) that features diffusion-coupled reactions between enzymes and electron carriers (quinones). Lipid unsaturation also modulated mitochondrial respiration in engineered budding yeast strains. Thus, diffusion in the ETC may serve as an evolutionary constraint for lipid composition in respiratory membranes.

Link: doi.org/10.1126/science.aat7925

publications
cells, bacteria, basic science
157
Frontiers in Psychiatry

Lipidomics in Major Depressive Disorder

Andreas Walther, Carlo V Cannistraci, Kai Simons, Claudio Durán, Mathias J Gerl, Susanne Wehrli, Clemens Kirschbaum

Omic sciences coupled with novel computational approaches such as machine intelligence offer completely new approaches to major depressive disorder (MDD) research. The complexity of MDD’s pathophysiology is being integrated into studies examining MDD’s biology within the omic fields. Lipidomics, as a late-comer among other omic fields, is increasingly being recognized in psychiatric research because it has allowed the investigation of global lipid perturbations in patients suffering from MDD and indicated a crucial role of specific patterns of lipid alterations in the development and progression of MDD. Combinatorial lipid-markers with high classification power are being developed in order to assist MDD diagnosis, while rodent models of depression reveal lipidome changes and thereby unveil novel treatment targets for depression. In this systematic review, we provide an overview of current breakthroughs and future trends in the field of lipidomics in MDD research and thereby paving the way for precision medicine in MDD.

Link: doi.org/10.3389/fpsyt.2018.00459

publications
biomarker, neuro
158
Scientific Reports

Cholesterol is Inefficiently Converted to Cholesteryl Esters in the Blood of Cardiovascular Disease Patients

Mathias J Gerl, Winchil L C Vaz, Neuza Domingues, Christian Klose, Michal A Surma, Júlio L Sampaio, Manuel S Almeida, Gustavo Rodrigues, Pedro Araújo-Gonçalves, Jorge Ferreira, Claudia Borbinha, João P Marto, Miguel Viana-Baptista, Kai Simons, Otilia V Vieira

Shotgun lipidomic analysis of 203 lipids in 13 lipid classes performed on blood plasma of donors who had just suffered an acute coronary syndrome (ACS, n = 74), or an ischemic stroke (IS, n = 21), or who suffer from stable angina pectoris (SAP, n = 78), and an age-matched control cohort (n = 52), showed some of the highest inter-lipid class correlations between cholesteryl esters (CE) and phosphatidylcholines (PC) sharing a common fatty acid. The concentration of lysophospatidylcholine (LPC) and ratios of concentrations of CE to free cholesterol (Chol) were also lower in the CVD cohorts than in the control cohort, indicating a deficient conversion of Chol to CE in the blood plasma in the CVD subjects. A non-equilibrium reaction quotient, Q′, describing the global homeostasis of cholesterol as manifested in the blood plasma was shown to have a value in the CVD cohorts (QACS = 0.217 ± 0.084; QIS = 0.201 ± 0.084; QSAP = 0.220 ± 0.071) that was about one third less than in the control cohort (QControl = 0.320 ± 0.095, p < 1 × 10−4), suggesting its potential use as a rapid predictive/diagnostic measure of CVD-related irregularities in cholesterol homeostasis.

Link: doi.org/10.1038/s41598-018-33116-4

publications
human, plasma/serum, clinical, biomarker, cvd
159
Neurochemistry International

Increased brain docosahexaenoic acid has no effect on the resolution of neuroinflammation following intracerebroventricular lipopolysaccharide injection

Marc-Olivier Trépanier, Kathryn E Hopperton, Vanessa Giuliano, Mojgan Masoodi, Richard P Bazinet

Resolution of inflammation in the periphery was once thought to be a passive process, but new research now suggests it is an active process mediated by specialized pro-resolving lipid mediators (SPM) derived from omega-3 polyunsaturated fatty acids (n-3 PUFA). However, this has yet to be illustrated in neuroinflammation. The purpose of this study was to measure resolution of neuroinflammation and to test whether increasing brain docosahexaenoic acid (DHA) affects the resolution of neuroinflammation. C57Bl/6 mice, fat-1 mice and their wildtype littermates, fed either fish oil or safflower oil, received lipopolysaccharide (LPS) in the left lateral ventricle. Animals were then euthanized at various time points for immunohistochemistry, gene expression, and lipidomic analyses. Peak microglial activation was observed at 5 days post-surgery and the resolution index was 10 days. Of the approximately 350 genes significantly changed over the 28 days post LPS injection, 130 were uniquely changed at 3 days post injection. No changes were observed in the bioactive mediator pools. However, a few lysophospholipid species were decreased at 24hr post surgery. When brain DHA is increased, microglial cell density did not resolve faster and did not alter gene expression. In conclusion, resolution of neuroinflammation appears to be independent of SPM. Increasing brain DHA had no effect in this model.

Link: doi.org/10.1016/j.neuint.2018.05.010

publications
organ/tissue, inflammation, mouse, diet, neuro, immuno
160
Journal of Biological Chemistry

An oxanthroquinone derivative that disrupts RAS plasma membrane localization inhibits cancer cell growth

Lingxiao Tan, Kwang-Jin Cho, Pratik Neupane, Robert J Capon, John F Hancock

Oncogenic RAS proteins are commonly expressed in human cancer. To be functional, RAS proteins must undergo post-translational modification and localize to the plasma membrane (PM). Therefore, compounds that prevent RAS PM targeting have potential as putative RAS inhibitors. Here we examine the mechanism of action of oxanthroquinone G01 (G01), a recently described inhibitor of KRAS PM localization. We show that G01 mislocalizes HRAS and KRAS from the PM with similar potency and disrupts the spatial organization of RAS proteins remaining on the PM. G01 also inhibited recycling of epidermal growth factor receptor and transferrin receptor, but did not impair internalization of cholera toxin, indicating suppression of recycling endosome function. In searching for the mechanism of impaired endosomal recycling we observed that G01 also enhanced cellular sphingomyelin (SM) and ceramide levels and disrupted the localization of several lipid and cholesterol reporters, suggesting that the G01 molecular target may involve SM metabolism. Indeed, G01 exhibited potent synergy with other compounds that target SM metabolism in KRAS localization assays. Furthermore, G01 significantly abrogated RAS-RAF-MAPK signaling in MDCK cells expressing constitutively activated, oncogenic mutant RASG12V. G01 also inhibited the proliferation of RAS-less mouse embryo fibroblasts (MEFs) expressing oncogenic mutant KRASG12V or KRASG12D but not RAS-less MEFs expressing oncogenic mutant BRAFV600E. Consistent with these effects, G01 selectively inhibited the proliferation of KRAS-transformed pancreatic, colon, and endometrial cancer cells. Taken together, these results suggest that G01 should undergo further evaluation as a potential anti-RAS therapeutic.

Link: doi.org/10.1074/jbc.RA118.003907

publications
other mammals, cells, pharma, cancer
161
npj Vaccines

Activation of the endoplasmic reticulum stress sensor IRE1α by the vaccine adjuvant AS03 contributes to its immunostimulatory properties

Charlotte Givord, Iain Welsby, Sophie Detienne, Séverine Thomas, Assiya Assabban, Viviana Lima Silva, Céline Molle, Romain Gineste, Marjorie Vermeersch, David Perez-Morga, Oberdan Leo, Catherine Collignon, Arnaud M Didierlaurent, Stanislas Goriely

The oil-in-water emulsion Adjuvant System 03 (AS03) is one of the few adjuvants used in licensed vaccines. Previous work indicates that AS03 induces a local and transient inflammatory response that contributes to its adjuvant effect. However, the molecular mechanisms involved in its immunostimulatory properties are ill-defined. Upon intramuscular injection in mice, AS03 elicited a rapid and transient downregulation of lipid metabolism-related genes in the draining lymph node. In vitro, these modifications were associated with profound changes in lipid composition, alteration of endoplasmic reticulum (ER) morphology and activation of the unfolded protein response pathway. In vivo, treatment with a chemical chaperone or deletion of the ER stress sensor kinase IRE1α in myeloid cells decreased AS03-induced cytokine production and its capacity to elicit high affinity antigen-specific antibodies. In summary, our results indicate that IRE1α is a sensor for the metabolic changes induced by AS03 in monocytic cells and may constitute a canonical pathway that could be exploited for the design of novel vaccine adjuvants.

Link: doi.org/10.1038/s41541-018-0058-4

publications
inflammation, mouse, cells, pharma, immuno
162
Patent

Methods and systems for metabolite and/or lipid-based detection of colorectal cancer and/or adenomatous polyps

Marko Bitenc, Kristi Kruusmaa, Paola Hurtado-Castillo, Ana M Jiménez-Girón, Rosa Argamasilla-Martinez, Andreu Fabregat-Rossel, Antonio J Adsuar-Gomez, Juan Martinez-Barea, Christian Hense, Patricia Rodríguez-Gómez, Ángela Peralbo-Molina, Jorge Casado-Agrelo, Alejandro Sánchez-Brotons, Christina Pavón-Solís, Rosa M Delgado-Sánchez

Described herein are sets of metabolite and lipid (e.g., fatty acid) markers that can be used in the detection of early stage colorectal cancer and/or early development of adenomatous polyps. Presented herein are illustrative pathology-linked panels. In certain embodiments, the markers presented herein (or subsets thereof) are used as a panel for detecting either colorectal cancer or adenomatous polyps at the same time. The markers presented herein include metabolites and lipids (e.g., fatty acid) freely detectable and accurately quantifiable in human serum. In certain embodiments, the sample may be plasma, urine, saliva, whole blood, dried blood spot or dried serum spot.

Link: freepatentsonline.com/y2017/0343567.html

patents
human, blood, plasma/serum, biomarker, cancer, method
163
Neuron

ER Lipid Defects in Neuropeptidergic Neurons Impair Sleep Patterns in Parkinson’s Disease

Jorge S Valadas, Giovanni Esposito, Dirk Vandekerkhove, Katarzyna Miskiewicz, Liesbeth Deaulmerie, Susanna Raitano, Philip Seibler, Christine Klein, Patrik Verstreken

Parkinson’s disease patients report disturbed sleep patterns long before motor dysfunction. Here, in parkin and pink1 models, we identify circadian rhythm and sleep pattern defects and map these to specific neuropeptidergic neurons in fly models and in hypothalamic neurons differentiated from patient induced pluripotent stem cells (iPSCs). Parkin and Pink1 control the clearance of mitochondria by protein ubiquitination. Although we do not observe major defects in mitochondria of mutant neuropeptidergic neurons, we do find an excess of endoplasmic reticulum-mitochondrial contacts. These excessive contact sites cause abnormal lipid trafficking that depletes phosphatidylserine from the endoplasmic reticulum (ER) and disrupts the production of neuropeptide-containing vesicles. Feeding mutant animals phosphatidylserine rescues neuropeptidergic vesicle production and acutely restores normal sleep patterns in mutant animals. Hence, sleep patterns and circadian disturbances in Parkinson’s disease models are explained by excessive ER-mitochondrial contacts, and blocking their formation or increasing phosphatidylserine levels rescues the defects in vivo.

Link: doi.org/10.1016/j.neuron.2018.05.022

publications
organ/tissue, organelle, insects, neuro
164
Biochemical Journal

A phosphatidic acid binding protein is important for lipid homeostasis and adaption to anaerobic biofilm conditions in Pseudomonas aeruginosa

Maike K Groenewold, Marco Massmig, Stefanie Hebecker, Linna Danne, Zofia Magnowska, Manfred Nimtz, Franz Narberhaus, Dieter Jahn, Dirk W Heinz, Lothar Jänsch, Jürgen Moser

A quantitative Pseudomonas aeruginosa proteomics approach revealed increased abundance of the so far uncharacterized protein PA3911 in anaerobic biofilms grown under conditions of the cystic fibrosis lung. Physiological relevance of ORF PA3911 was demonstrated, inter alia, using phenotype microarray experiments. The mutant strain showed increased susceptibility in the presence of antimicrobials (minocycline, nafcillin, oxacillin, chloramphenicol, thiamphenicol), enhanced twitching motility and significantly impaired biofilm formation. PA3911 is a soluble, cytoplasmic protein in P. aeruginosa. In protein-lipid overlay experiments, purified PA3911 bound specifically to phosphatidic acid (PA), the central hub of phospholipid metabolism. Structure-guided site-directed mutagenesis was used to explore the proposed ligand binding cavity of PA3911. Proteins variant of Leu56, Leu58, Val69 and Leu114 were shown to impair PA interaction. A comparative shotgun lipidomics approach demonstrated a multifaceted response of P. aeruginosa to anaerobic conditions at the lipid head group and fatty acid level. Lipid homeostasis in the PA3911 mutant strain was imbalanced with respect to lysophosphatidylcholine, phosphatidylcholine and diacylglycerol under anaerobic and/or aerobic conditions. The impact of the newly identified PA binding protein on lipid homeostasis and the related macroscopic phenotypes of P. aeruginosa are discussed.

Link: doi.org/10.1042/BCJ20180257

publications
cells, bacteria, basic science
165
Phytochemical Analysis

Dereplication of plant phenolics using a mass‐spectrometry database independent method

Ricardo M Borges, Rahil Taujale, Juliana Santana de Souza, Thaís de Andrade Bezerra, Eder Lana e Silva, Ronny Herzog, Francesca V Ponce, Jean-Luc Wolfender, Arthur S Edison

Dereplication, an approach to sidestep the efforts involved in the isolation of known compounds, is generally accepted as being the first stage of novel discoveries in natural product research. It is based on metabolite profiling analysis of complex natural extracts.

To present the application of LipidXplorer for automatic targeted dereplication of phenolics in plant crude extracts based on direct infusion high‐resolution tandem mass spectrometry data.

LipidXplorer uses a user‐defined molecular fragmentation query language (MFQL) to search for specific characteristic fragmentation patterns in large data sets and highlight the corresponding metabolites. To this end, MFQL files were written to dereplicate common phenolics occurring in plant extracts. Complementary MFQL files were used for validation purposes.

New MFQL files with molecular formula restrictions for common classes of phenolic natural products were generated for the metabolite profiling of different representative crude plant extracts. This method was evaluated against an open‐source software for mass‐spectrometry data processing (MZMine®) and against manual annotation based on published data.

The targeted LipidXplorer method implemented using common phenolic fragmentation patterns, was found to be able to annotate more phenolics than MZMine® that is based on automated queries on the available databases. Additionally, screening for ascarosides, natural products with unrelated structures to plant phenolics collected from the nematode Caenorhabditis elegans, demonstrated the specificity of this method by cross‐testing both groups of chemicals in both plants and nematodes.

Link: doi.org/10.1002/pca.2773

publications
software
166
Proteomics

How Can Omic Science be Improved?

Kai Simons

One of the promises of multiomic analysis was to transform the clinical diagnostics to deliver much more exact phenotyping of disease states. However, despite enormous investments, the transformation of clinical routine has not taken place. There are many reasons for this lack of success but one is the failure to deliver quantitative and reproducible data. This failure is not only impeding progress in clinical phenotyping but also in the application of omic science in systems biology. The focus in this Viewpoint will be on lipidomics but the lessons learned are generally applicable

Link: doi.org/10.1002/pmic.201800039

publications
method
167
Cancer Research

Organelle-derived acetyl-CoA promotes prostate cancer cell survival, migration, and metastasis via activation of calmodulin kinase II

Guoyu Yu, Chien-Jui Cheng, Song-Chang Lin, Yu-Chen Lee, Daniel E Frigo, Li-Yuan Yu-Lee, Gary E Gallick, Mark A Titus, Leta K Nutt, Sue-Hwa Lin

Although emerging evidence suggests a potential role of calcium/calmodulin-dependent kinase II (CaMKII) in prostate cancer (PCa), its role in PCa tumorigenesis is largely unknown. Here we examine whether the acetyl CoA-CaMKII pathway, first described in frog oocytes, promotes PCa tumorigenesis. In human PCa specimens, metastatic PCa expressed higher levels of active CaMKII compared to localized PCa. Correspondingly, basal CaMKII activity was significantly higher in the more tumorigenic PC3 and PC3-mm2 cells relative to the less tumorigenic LNCaP and C4-2B4 cells. Deletion of CaMKII by CRISPR/Cas9 in PC3-mm2 cells abrogated cell survival under low-serum conditions, anchorage-independent growth and cell migration; overexpression of constitutively active CaMKII in C4-2B4 cells promoted these phenotypes. In an animal model of PCa metastasis, genetic ablation of CaMKII reduced PC3-mm2 cell metastasis from the prostate to the lymph nodes. Knockdown of the acetyl-CoA transporter carnitine acetyltransferase (CRAT) abolished CaMKII activation, providing evidence that acetyl-CoA generated from organelles is a major activator of CaMKII. Genetic deletion of the β-oxidation rate-limiting enzyme ACOX family proteins decreased CaMKII activation, while overexpression of ACOXI increased CaMKII activation. Overall, our studies identify active CaMKII as a novel connection between organelle β-oxidation and acetyl-CoA transport with cell survival, migration, and PCa metastasis.

Link: doi.org/10.1158/0008-5472.CAN-17-2392

publications
human, cells, cancer
168
Molecular and Cellular Biology

Sphingomyelin Metabolism Is a Regulator of K-Ras Function

Dharini van der Hoeven, Kwang-Jin Cho, Yong Zhou, Xiaoping Ma, Wei Chen, Ali Naji, Dina Montufar-Solis, Yan Zuo, Sarah E Kovar, Kandice R Levental, Jeffrey A Frost, Ransome van der Hoeven, John F Hancock

K-Ras must localize to the plasma membrane (PM) for biological activity. We show here that multiple acid sphingomyelinase (ASM) inhibitors, including tricyclic antidepressants, mislocalized phosphatidylserine (PtdSer) and K-RasG12V from the PM, resulting in abrogation of K-RasG12V signaling and potent, selective growth inhibition of mutant K-Ras-transformed cancer cells. Concordantly, in nude mice, the ASM inhibitor fendiline decreased the rate of growth of oncogenic K-Ras-expressing MiaPaCa-2 tumors but had no effect on the growth of the wild-type K-Ras-expressing BxPC-3 tumors. ASM inhibitors also inhibited activated LET-60 (a K-Ras ortholog) signaling in Caenorhabditis elegans, as evidenced by suppression of the induced multivulva phenotype. Using RNA interference against C. elegans genes encoding other enzymes in the sphingomyelin (SM) biosynthetic pathway, we identified 14 enzymes whose knockdown strongly or moderately suppressed the LET-60 multivulva phenotype. In mammalian cells, pharmacological agents that target these enzymes all depleted PtdSer from the PM and caused K-RasG12V mislocalization. These effects correlated with changes in SM levels or subcellular distribution. Selected compounds, including sphingosine kinase inhibitors, potently inhibited the proliferation of oncogenic K-Ras-expressing pancreatic cancer cells. In conclusion, these results show that normal SM metabolism is critical for K-Ras function, which may present therapeutic options for the treatment of K-Ras-driven cancers.

Link: doi.org/doi:10.1128/MCB.00373-17

publications
other mammals, cells, cancer
169
Cell

Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity

Ioannis Mitroulis, Klara Ruppova, Baomei Wang, Lan-Sun Chen, Michal Grzybek, Tatyana Grinenko, Anne Eugster, Maria Troullinaki, Alessandra Palladini, Ioannis Kourtzelis, Antonios Chatzigeorgiou, Andreas Schlitzer, Marc Beyer, Leo A B Joosten, Berend Isermann, Mathias Lesche, Andreas Petzold, Kai Simons, Ian Henry, Andreas Dahl, Joachim L Schultze, Ben Wielockx, Nicola Zamboni, Peter Mirtschink, Ünal Coskun, George Hajishengallis, Mihai G Netea, Triantafyllos Chavakis

Trained innate immunity fosters a sustained favorable response of myeloid cells to a secondary challenge, despite their short lifespan in circulation. We thus hypothesized that trained immunity acts via modulation of hematopoietic stem and progenitor cells (HSPCs). Administration of β-glucan (prototypical trained-immunity-inducing agonist) to mice induced expansion of progenitors of the myeloid lineage, which was associated with elevated signaling by innate immune mediators, such as IL-1β and granulocyte-macrophage colony-stimulating factor (GM-CSF), and with adaptations in glucose metabolism and cholesterol biosynthesis. The trained-immunity-related increase in myelopoiesis resulted in a beneficial response to secondary LPS challenge and protection from chemotherapy-induced myelosuppression in mice. Therefore, modulation of myeloid progenitors in the bone marrow is an integral component of trained immunity, which to date, was considered to involve functional changes of mature myeloid cells in the periphery.

Link: doi.org/10.1016/j.cell.2017.11.034

publications
mouse, cells, immuno
170
PLOS genetics

Adipose tissue ATGL modifies the cardiac lipidome in pressure-overload-induced left ventricular failure

Janek Salatzki, Anna Foryst-Ludwig, Kajetan Bentele, Annelie Blumrich, Elia Smeir, Zsofia Ban, Sarah Brix, Jana Grune, Niklas Beyhoff, Robert Klopfleisch, Sebastian Dunst, Michal A Surma, Christian Klose, Michael Rothe, Frank R Heinzel, Alexander Krannich, Erin E Kershaw, Dieter Beule, P Christian Schulze, Nikolaus Marx, Ulrich Kintscher

Adipose tissue lipolysis occurs during the development of heart failure as a consequence of chronic adrenergic stimulation. However, the impact of enhanced adipose triacylglycerol hydrolysis mediated by adipose triglyceride lipase (ATGL) on cardiac function is unclear. To investigate the role of adipose tissue lipolysis during heart failure, we generated mice with tissue-specific deletion of ATGL (atATGL-KO). atATGL-KO mice were subjected to transverse aortic constriction (TAC) to induce pressure-mediated cardiac failure. The cardiac mouse lipidome and the human plasma lipidome from healthy controls (n = 10) and patients with systolic heart failure (HFrEF, n = 13) were analyzed by MS-based shotgun lipidomics. TAC-induced increases in left ventricular mass (LVM) and diastolic LV inner diameter were significantly attenuated in atATGL-KO mice compared to wild type (wt) -mice. More importantly, atATGL-KO mice were protected against TAC-induced systolic LV failure. Perturbation of lipolysis in the adipose tissue of at ATGL-KO mice resulted in the prevention of the major cardiac lipidome changes observed after TAC in wt-mice. Profound changes occurred in the lipid class of phosphatidylethanolamines (PE) in which multiple PE-species were markedly induced in failing wt-hearts, which was attenuated in atATGL-KO hearts. Moreover, selected heart failure-induced PE species in mouse hearts were also induced in plasma samples from patients with chronic heart failure. TAC-induced cardiac PE induction resulted in decreased PC/ PE-species ratios associated with increased apoptotic marker expression in failing wt-hearts, a process absent in atATGL-KO hearts. Perturbation of adipose tissue lipolysis by ATGL-deficiency ameliorated pressure-induced heart failure and the potentially deleterious cardiac lipidome changes that accompany this pathological process, namely the induction of specific PE species. Non-cardiac ATGL-mediated modulation of the cardiac lipidome may play an important role in the pathogenesis of chronic heart failure.

Link: doi.org/10.1371/journal.pgen.1007171

publications
human, organ/tissue, mouse, plasma/serum, biomarker, cvd
171
Current Biology

Cell Size and Growth Rate Are Modulated by TORC2-Dependent Signals

Rafael Lucena, Maria Alcaide-Gavilán, Katherine Schubert, Maybo He, Matthew G Domnauer, Catherine Marquer, Christian Klose, Michal A Surma, Douglas R Kellogg

The size of all cells, from bacteria to vertebrates, is proportional to the growth rate set by nutrient availability, but the underlying mechanisms are unknown. Here, we show that nutrients modulate cell size and growth rate via the TORC2 signaling network in budding yeast. An important function of the TORC2 network is to modulate synthesis of ceramide lipids, which play roles in signaling. TORC2-dependent control of ceramide signaling strongly influences both cell size and growth rate. Thus, cells that cannot make ceramides fail to modulate their growth rate or size in response to changes in nutrients. PP2A associated with the Rts1 regulatory subunit (PP2A[Rts1]) is embedded in a feedback loop that controls TORC2 signaling and helps set the level of TORC2 signaling to match nutrient availability. Together, the data suggest a model in which growth rate and cell size are mechanistically linked by ceramide-dependent signals arising from the TORC2 network.

Link: doi.org/10.1016/j.cub.2017.11.069

publications
cells, yeast, basic science
172
Cell Reports

Serine-Dependent Sphingolipid Synthesis Is a Metabolic Liability of Aneuploid Cells

Sunyoung Hwang, H Tobias Gustafsson, Ciara O'Sullivan, Gianna Bisceglia, Xinhe Huang, Christian Klose, Andrej Shevchenko, Robert C Dickson, Paola Cavaliere, Noah Dephoure, Eduardo M Torres

Aneuploidy disrupts cellular homeostasis. However, the molecular mechanisms underlying the physiological responses and adaptation to aneuploidy are not well understood. Deciphering these mechanisms is important because aneuploidy is associated with diseases, including intellectual disability and cancer. Although tumors and mammalian aneuploid cells, including several cancer cell lines, show altered levels of sphingolipids, the role of sphingolipids in aneuploidy remains unknown. Here, we show that ceramides and long-chain bases, sphingolipid molecules that slow proliferation and promote survival, are increased by aneuploidy. Sphingolipid levels are tightly linked to serine synthesis, and inhibiting either serine or sphingolipid synthesis can specifically impair the fitness of aneuploid cells. Remarkably, the fitness of aneuploid cells improves or deteriorates upon genetically decreasing or increasing ceramides, respectively. Combined targeting of serine and sphingolipid synthesis could be exploited to specifically target cancer cells, the vast majority of which are aneuploid.

Link: doi.org/10.1016/j.celrep.2017.11.103

publications
cells, yeast, cancer
173
Journal of Lipid Research

Harmonizing lipidomics: NIST interlaboratory comparison exercise for lipidomics using SRM 1950–Metabolites in Frozen Human Plasma

John A Bowden, Alan Heckert, Candice Z Ulmer, Christina M Jones, Jeremy P Koelmel, Laila Abdullah, Linda Ahonen, Yazen Alnouti, Aaron M Armando, John M Asara, Takeshi Bamba, John R Barr, Jonas Bergquist, Christoph H Borchers, Joost Brandsma, Susanne B Breitkopf, Tomas Cajka, Amaury Cazenave-Gassiot, Antonio Checa, Michelle A Cinel, Romain A Colas, Serge Cremers, Edward A Dennis, James E Evans, Alexander Fauland, Oliver Fiehn, Michael S Gardner, Timothy J Garrett, Katherine H Gotlinger, Jun Han, Yingying Huang, Aveline Huipeng Neo, Tuulia Hyötyläinen, Yoshihiro Izumi, Hongfeng Jiang, Houli Jiang, Jiang Jiang, Maureen Kachman, Reiko Kiyonami, Kristaps Klavins, Christian Klose, Harald C Köfeler, Johan Kolmert, Therese Koal, Grielof Koster, Zsuzsanna Kuklenyik, Irwin J Kurland, Michael Leadley, Karen Lin, Krishna Rao Maddipati, Danielle McDougall, Peter J Meikle, Natalie A Mellett, Cian Monnin, M Arthur Moseley, Renu Nandakumar, Matej Oresic, Rainey Patterson, David Peake, Jason S Pierce, Martin Post, Anthony D Postle, Rebecca Pugh, Yunping Qiu, Oswald Quehenberger, Parsram Ramrup, Jon Rees, Barbara Rembiesa, Denis Reynaud, Mary R Roth, Susanne Sales, Kai Schuhmann, Michal Laniado Schwartzman, Charles N Serhan, Andrej Shevchenko, Stephen E Somerville, Lisa St. John-Williams, Michal A Surma, Hiroaki Takeda, Rhishikesh Thakare, J Will Thompson, Federico Torta, Alexander Triebl, Martin Trötzmüller, S J Kumari Ubhayasekera, Dajana Vuckovic, Jacquelyn M Weir, Ruth Welti, Markus R Wenk, Craig E Wheelock, Libin Yao, Min Yuan, Xueqing H Zhao, Senlin Zhou

As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950–Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each laboratory using a different lipidomics workflow. A total of 1,527 unique lipids were measured across all laboratories and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks for intra- and interlaboratory quality control and method validation. These analyses were performed using nonstandardized laboratory-independent workflows. The consensus locations were also compared with a previous examination of SRM 1950 by the LIPID MAPS consortium. While the central theme of the interlaboratory study was to provide values to help harmonize lipids, lipid mediators, and precursor measurements across the community, it was also initiated to stimulate a discussion regarding areas in need of improvement.

Link: doi.org/10.1194/jlr.M079012

publications
human, plasma/serum, method
174
Nature Communications

Machine learning meets complex networks via coalescent embedding in the hyperbolic space

Alessandro Muscoloni, Josephine M Thomas, Sara Ciucci, Ginestra Bianconi, Carlo V Cannistraci

Physicists recently observed that realistic complex networks emerge as discrete samples from a continuous hyperbolic geometry enclosed in a circle: the radius represents the node centrality and the angular displacement between two nodes resembles their topological proximity. The hyperbolic circle aims to become a universal space of representation and analysis of many real networks. Yet, inferring the angular coordinates to map a real network back to its latent geometry remains a challenging inverse problem. Here, we show that intelligent machines for unsupervised recognition and visualization of similarities in big data can also infer the network angular coordinates of the hyperbolic model according to a geometrical organization that we term “angular coalescence.” Based on this phenomenon, we propose a class of algorithms that offers fast and accurate “coalescent embedding” in the hyperbolic circle even for large networks. This computational solution to an inverse problem in physics of complex systems favors the application of network latent geometry techniques in disciplines dealing with big network data analysis including biology, medicine, and social science.

Link: doi.org/10.1038/s41467-017-01825-5

publications
software
175
Patent

Means and methods for treatment of early-onset Parkinson’s disease

Patrik Verstreken, Vanessa A Morais, Melissa Vos

This application relates to the field of neurodegenerative diseases, more particularly to the field of Parkinson’s disease. In particular, the disclosure describes that inhibitors reducing FAS activity can be used for treatment of Parkinson’s disease, in particular, the treatment of patients suffering from Parkinson’s disease having loss of function mutations in PINK1 or PARKIN genes.

Link: freepatentsonline.com/y2017/0319610.html

patents
organ/tissue, organelle, pharma, insects, neuro, method
176
Science Advances

ω-3 polyunsaturated fatty acids direct differentiation of the membrane phenotype in mesenchymal stem cells to potentiate osteogenesis

Kandice R Levental, Michal A Surma, Allison D Skinkle, Joseph H Lorent, Yong Zhou, Christian Klose, Jeffrey T Chang, John F Hancock, Ilya Levental

Mammalian cells produce hundreds of dynamically regulated lipid species that are actively turned over and trafficked to produce functional membranes. These lipid repertoires are susceptible to perturbations from dietary sources, with potentially profound physiological consequences. However, neither the lipid repertoires of various cellular membranes, their modulation by dietary fats, nor their effects on cellular phenotypes have been widely explored. We report that differentiation of human mesenchymal stem cells (MSCs) into osteoblasts or adipocytes results in extensive remodeling of the plasma membrane (PM), producing cell-specific membrane compositions and biophysical properties. The distinct features of osteoblast PMs enabled rational engineering of membrane phenotypes to modulate differentiation in MSCs. Specifically, supplementation with docosahexaenoic acid (DHA), a lipid component characteristic of osteoblast membranes, induced broad lipidomic remodeling in MSCs that reproduced compositional and structural aspects of the osteoblastic PM phenotype. The PM changes induced by DHA supplementation potentiated osteogenic differentiation of MSCs concurrent with enhanced Akt activation at the PM. These observations prompt a model wherein the DHA-induced lipidome leads to more stable membrane microdomains, which serve to increase Akt activity and thereby enhance osteogenic differentiation. More broadly, our investigations suggest a general mechanism by which dietary fats affect cellular physiology through remodeling of membrane lipidomes, biophysical properties, and signaling.

Link: doi.org/10.1126/sciadv.aao1193

publications
human, other mammals, cells, organelle, diet, basic science
177
npj systems biology and applications

Transcriptomics-driven lipidomics (TDL) identifies the microbiome-regulated targets of ileal lipid metabolism

Anirikh Chakrabarti, Mathieu Membrez, Delphine Morin‐Rivron, Jay Siddharth, Chieh J Chou, Hugues Henry, Stephen Bruce, Sylviane Metairon, Frederic Raymond, Bertrand Betrisey, Carole Loyer, Scott J Parkinson, Mojgan Masoodi

The gut microbiome and lipid metabolism are both recognized as essential components in the maintenance of metabolic health. The mechanisms involved are multifactorial and (especially for microbiome) poorly defined. A strategic approach to investigate the complexity of the microbial influence on lipid metabolism would facilitate determination of relevant molecular mechanisms for microbiome-targeted therapeutics. E. coli is associated with obesity and metabolic syndrome and we used this association in conjunction with gnotobiotic models to investigate the impact of E. coli on lip