Lipidomics Resource Center

All science is just as good, as the research which precedes it. This platform helps you to discover lipidomics publications and empower your lipid research.

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  1. Translational Oncology, 2020

    1Mass 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

    Abstract

    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.

    doi.org/10.1016/j.tranon.2020.100807

    academia
    organ/tissue, human, clinical, cancer
  2. Journal of Cellular and Molecular Medicine, 2020

    2Targeting 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

    Abstract

    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.

    doi.org/10.1111/jcmm.15218

    academia
    human, cells, pharma, cancer
  3. Brain, 2020

    3Excess 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

    Abstract

    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.

    doi.org/10.1093/brain/awaa139

    academia
    organ/tissue, mouse, neuro
  4. Cells, 2020

    4Phosphoinositide Profile of the Mouse Retina

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

    Abstract

    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.

    doi.org/10.3390/cells9061417

    academia
    mouse, cells, basic science
  5. Scientific Reports, 2020

    5Avicin 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

    Abstract

    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.

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

    academia
    cells, other mammals, cancer
  6. The EMBO Journal, 2020

    6Dysfunctional 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

    Abstract

    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.

    doi.org/10.15252/embj.2019103812

    academia
    organ/tissue, mouse, cells, pharma
  7. Cellular and Molecular Life Sciences, 2020

    7Diacylglycerol 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

    Abstract

    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.

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

    academia
    human, cells, basic science
  8. Patent, 2020

    8Fusosome Compositions for Hematopoietic Stem Cell Deliver

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

    Abstract

    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.

    freepatentsonline.com/WO2020102485A1.html

    industry
    organelle, pharma, method
  9. Patent, 2020

    9Fusosome 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

    Abstract

    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.

    freepatentsonline.com/WO2020102503A2.html

    industry
    immuno, organelle, pharma, method
  10. Patent, 2020

    10Fusosome 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

    Abstract

    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.

    freepatentsonline.com/WO2020102499A2.html

    industry
    organelle, pharma, neuro, method
  11. nature chemical biology, 2020

    11Plasma 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

    Abstract

    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.

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

    academia
    human, organelle, basic science
  12. Cell Reports, 2020

    12The 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

    Abstract

    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.

    doi.org/10.1016/j.celrep.2020.107567

    academia
    yeast, organelle, basic science
  13. Microbial Biotechnology, 2020

    13Myriocin‐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

    Abstract

    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.

    doi.org/10.1111/1751-7915.13555

    academia
    cells, yeast, basic science
  14. nature communications, 2020

    14Lipidomic 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

    Abstract

    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.

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

    academia
    diet, organelle, other mammals, basic science
  15. Patent, 2020

    15Asparagine synthetase inhibitors and uses thereof

    Alessandra Boletta, Christine Podrini, Isaline Rowe

    Abstract

    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.

    freepatentsonline.com/WO2020049069A1.html

    industry
    mouse, cells, pharma
  16. nature oncogene, 2020

    16The 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

    Abstract

    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.

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

    academia
    human, cells, cancer
  17. Applied and Environmental Microbiology, 2020

    17Yeast 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

    Abstract

    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.

    doi.org/10.1128/AEM.02446-19

    academia
    cells, yeast, basic science
  18. Endocrine-Related Cancer, 2020

    18LDLR-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

    Abstract

    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.

    doi.org/10.1530/ERC-19-0095

    academia
    human, organ/tissue, cells, mouse, cancer
  19. The FEBS Journal, 2020

    19Sex‐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

    Abstract

    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.

    doi.org/10.1111/febs.15221

    academia
    mouse, cells, basic science
  20. Cell Reports, 2020

    20The 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

    Abstract

    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.

    doi.org/10.1016/j.celrep.2019.12.022

    academia
    cells, yeast, basic science
  21. International Journal of Molecular Sciences, 2020

    21Association 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

    Abstract

    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.

    doi.org/10.3390/ijms21020627

    academia
    cells, other mammals, basic science
  22. Cancer Research, 2020

    22Undermining 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

    Abstract

    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.

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

    academia
    human, cells, cancer
  23. British Journal of Pharmacology, 2020

    23Preclinical 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

    Abstract

    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.

    doi.org/10.1111/bph.14973

    academia
    clinical, organ/tissue, pharma, neuro, other mammals
  24. Patent, 2020

    24MicroRNA Targeting Agent for Treatment of Heart Disease

    Jaya Krishnan, Corinne Bischof

    Abstract

    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.

    freepatentsonline.com/WO2020002694A1.html

    industry
    organ/tissue, mouse, CVD
  25. Diabetes Care, 2019

    25Plasma 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

    Abstract

    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.

    doi.org/10.2337/dc19-1199

    academia
    human, clinical, biomarker, plasma/serum, diabetes
  26. Cell Reports, 2019

    26Suppressing 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

    Abstract

    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.

    doi.org/10.1016/j.celrep.2019.10.059

    academia
    yeast, organelle, basic science
  27. The Journal of Clinical Endocrinology & Metabolism, 2019

    27Shotgun 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

    Abstract

    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.

    doi.org/10.1210/clinem/dgz176

    academia
    human, clinical, organ/tissue, diet, plasma/serum, diabetes
  28. BBA Molecular and Cell Biology of Lipids, 2019

    28Pho85 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

    Abstract

    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.

    doi.org/10.1016/j.bbalip.2019.158557

    academia
    cells, yeast, basic science
  29. PLOS Biology, 2019

    29Machine 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

    Abstract

    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.

    doi.org/10.1371/journal.pbio.3000443

    academia
    obesity, human, clinical, biomarker, plasma/serum
  30. Frontiers in Cell and Developmental Biology, 2019

    30Role 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

    Abstract

    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.

    doi.org/10.3389/fcell.2019.00226

    academia
    immuno, human, organelle
  31. nature communications, 2019

    31Genetic 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

    Abstract

    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.

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

    academia
    human, clinical, biomarker, plasma/serum, CVD
  32. Kidney international, 2019

    32Integrative 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

    Abstract

    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.

    doi.org/10.1016/j.kint.2019.07.025

    academia
    human, clinical, biomarker, plasma/serum, diabetes
  33. Molecular Cell, 2019

    33Osh 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

    Abstract

    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.

    doi.org/10.1016/j.molcel.2019.06.037

    academia
    cells, yeast, basic science
  34. Journal of Cell Biology, 2019

    34Lipid 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

    Abstract

    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.

    doi.org/10.1083/jcb.201803153

    academia
    cells, other mammals, basic science
  35. Molecular Metabolism, 2019

    35Multi-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

    Abstract

    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.

    doi.org/10.1016/j.molmet.2019.05.011

    academia
    organ/tissue, clinical, biomarker, diabetes, other mammals
  36. BBA Molecular and Cell Biology of Lipids, 2019

    36The 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

    Abstract

    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.

    doi.org/10.1016/j.bbalip.2019.07.012

    academia
    human, cells, basic science
  37. Journal of the AHA, 2019

    37Coronary 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

    Abstract

    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.

    doi.org/10.1161/JAHA.119.012415

    academia
    human, clinical, plasma/serum, CVD
  38. Patent, 2019

    38Means and methods to treat dystonia

    Rose E Goodchild, Micheline Grillet

    Abstract

    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.

    freepatentsonline.com/y2019/0160184.html

    industry
    cells, fly, pharma, neuro, method
  39. Cell, 2019

    39CerS6-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

    Abstract

    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.

    doi.org/10.1016/j.cell.2019.05.008

    academia
    obesity, human, cells, mouse, diabetes
  40. Molecular Metabolism, 2019

    40Comprehensive 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

    Abstract

    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.

    doi.org/10.1016/j.molmet.2019.01.009

    academia
    obesity, clinical, organ/tissue, mouse, biomarker, diet, method
  41. BBA Biomembranes, 2019

    41Membrane cholesterol depletion reduces downstream signaling activity of the adenosine A2a receptor

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

    Abstract

    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.

    doi.org/10.1016/j.bbamem.2019.01.001

    academia
    human, organelle, basic science
  42. Nature Communications Biology, 2018

    42Dissection 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

    Abstract

    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.

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

    academia
    organ/tissue, mouse, basic science
  43. Patent, 2018

    43Compositions 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

    Abstract

    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.

    freepatentsonline.com/WO2018208728A1.html

    industry
    organelle, pharma, method
  44. Science, 2018

    44Viscous 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

    Abstract

    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.

    doi.org/10.1126/science.aat7925

    academia
    cells, bacteria, basic science
  45. White Paper Series, 2018

    45Unlocking the Power of Multiomics

    Henri Deda, Christian Klose, Kai Simons

    Abstract

    Multiomics approaches are on their way to revolutionize medicine and biology. Being major players in cardiovascular disease research, genomics and lipidomics are perfectly suited for a joint multiomics approach. Combining genomic risk prediction with lipidomic phenotyping will result in an effective payoff.

    This whitepaper will answer how linking the lipid phenotype to the genotype will improve performance and showcase immediate and future consequences for prevention, clinical diagnostics and drug research.

    www.lipotype.com/multiomics/

    white papers
    human, clinical, biomarker, plasma/serum, CVD
  46. Frontiers in Psychiatry, 2018

    46Lipidomics in Major Depressive Disorder

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

    Abstract

    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.

    doi.org/10.3389/fpsyt.2018.00459

    academia
    biomarker, neuro
  47. Scientific Reports, 2018

    47Cholesterol 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

    Abstract

    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.

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

    academia
    human, clinical, biomarker, plasma/serum, CVD
  48. Product development, 2018

    48Photodamaged dry facial skin from different ethnic groups

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

    Abstract
    Even though decades of moisturizer development have passed, dry facial skin remains a major concern for consumers. Thus, DSM’s aim was to understand more precisely the underlying biochemistry, particularly of the maturation of the stratum corneum and its relation to facial photodamage, skin pigmentation and ethnicity. In contrast to traditional research of skin analyte composition, a more revolutionary ‘omic’ approach was applied.
    www.lipotype.com/2018/08/royal-dsm/

    industry
    cosmetics, human, skin
  49. Journal of Biological Chemistry, 2018

    49An 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

    Abstract

    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.

    doi.org/10.1074/jbc.RA118.003907

    academia
    cells, pharma, other mammals, cancer
  50. npj Vaccines, 2018

    50Activation 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

    Abstract

    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.

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

    academia
    immuno, mouse, cells, pharma
  51. Patent, 2018

    51Methods 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

    Abstract

    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.

    freepatentsonline.com/y2017/0343567.html

    industry
    human, biomarker, blood, plasma/serum, cancer, method
  52. Neuron, 2018

    52ER 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

    Abstract

    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.

    doi.org/10.1016/j.neuron.2018.05.022

    academia
    organ/tissue, fly, organelle, neuro
  53. Biochemical Journal, 2018

    53A 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

    Abstract

    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.

    doi.org/10.1042/BCJ20180257

    academia
    cells, bacteria, basic science
  54. Product development, 2018

    54Lipid analysis for skin penetration properties of saturated phospholipids

    Dorothea Gutekunst, Christian Klose, Christoph Heidecke, Peter Van Hoogevest

    Abstract

    Lipoid conducted this novel study to investigate skin penetration properties of dermal formulations based on hydrogenated phospholipids. Common to all topically used phospholipids is their ability to interact with skin structures and the similarity to epidermal lipids. For the first time, the quantitative analysis of both exogenous phospholipids and endogenous skin lipids within a single measurement was demonstrated. The results confirm the properties of hydrogenated phospholipids to penetrate and accumulate in upper epidermal layers.

    www.lipotype.com/2018/05/lipoid/

    industry
    cosmetics, human, pharma, skin
  55. Phytochemical Analysis, 2018

    55Dereplication 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

    Abstract

    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.

    doi.org/10.1002/pca.2773

    academia
    software
  56. Proteomics, 2018

    56How Can Omic Science be Improved?

    Kai Simons

    Abstract

    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

    doi.org/10.1002/pmic.201800039

    academia
    method
  57. Cancer Research, 2018

    57Organelle-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

    Abstract

    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.

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

    academia
    human, cells, cancer
  58. Molecular and Cellular Biology, 2018

    58Sphingomyelin 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

    Abstract

    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.

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

    academia
    cells, other mammals, cancer
  59. Cell, 2018

    59Modulation 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

    Abstract

    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.

    doi.org/10.1016/j.cell.2017.11.034

    academia
    immuno, mouse, cells
  60. PLOS genetics, 2018

    60Adipose 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

    Abstract

    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.

    doi.org/10.1371/journal.pgen.1007171

    academia
    human, organ/tissue, biomarker, mouse, plasma/serum, CVD
  61. Current Biology, 2017

    61Cell 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

    Abstract

    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.

    doi.org/10.1016/j.cub.2017.11.069

    academia
    cells, yeast, basic science
  62. Cell Reports, 2017

    62Serine-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

    Abstract

    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.

    doi.org/10.1016/j.celrep.2017.11.103

    academia
    cells, yeast, cancer
  63. Journal of Lipid Research, 2017

    63Harmonizing 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

    Abstract

    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.

    doi.org/10.1194/jlr.M079012

    academia
    human, plasma/serum, method
  64. Nature Communications, 2017

    64Machine learning meets complex networks via coalescent embedding in the hyperbolic space

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

    Abstract

    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.

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

    academia
    software
  65. Patent, 2017

    65Means and methods for treatment of early-onset Parkinson’s disease

    Patrik Verstreken, Vanessa A Morais, Melissa Vos

    Abstract

    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.

    freepatentsonline.com/y2017/0319610.html

    industry
    organ/tissue, fly, organelle, pharma, neuro, method
  66. Science Advances, 2017

    66ω-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

    Abstract

    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.

    doi.org/10.1126/sciadv.aao1193

    academia
    human, cells, diet, organelle, other mammals, basic science
  67. Hormone and Metabolic Research, 2017

    67Lipidomic Changes in Skeletal Muscle in Patients after Biliopancreatic Diversion

    Carola S Mehnert, Juergen Graessler, Virginia Kamvissi-Lorenz, Lidia Castagneto Gissey, James R Casella Mariolo, Giovanni Casella, Geltrude Mingrone, Stefan R Bornstein

    Abstract

    The mechanisms behind the fast improvements of insulin sensitivity and release of the diabetic metabolic state after bariatric surgery are still not completely understood. To further elucidate the effects on the individual cellular level, we applied mass spectrometry to investigate the changes in the lipidomic profile of skeletal muscle cells before and after biliopancreatic diversion in six patients. We found a decrease in lipid storage species, mainly triacylglycerides (e. g., TAG 52:2 from 19.84 to 13.26 mol%; p=0.028), and an increase in structural and signaling lipids, including phosphatidylcholines [PC 36:2 (18:1/18:1) from 0.12 to 0.65 mol%; p=0.046], phosphatidylinositols (PI 36:2 from 0.008 to 0.039 mol%; p=0.046), and cardiolipins (CL 72:8 from 0.16 to 1.22 mol%; p=0.043). The proportional increase in structural lipids was directly and the decrease in TAGs was inversely correlated to improved post-operative insulin sensitivity, measured by euglycemic hyperinsulinemic clamp. Thus, short-term recovery of insulin sensitivity after biliopancreatic diversion may, beside gut hormonal adaptation, mechanical factors, shifts in the gut microbiome, and changes in bile acid and phospholipid metabolism, additionally be attributed to a metabolic recovery of skeletal muscle cells, reflected by normalization of the cellular lipidomic profile. Further studies are needed to investigate whether improved insulin sensitivity of skeletal muscle might be directly associated with the degradation of ectopic triglycerides, thereby reducing the reservoir of lipotoxic intermediates, which might interfere with insulin signaling and hamper mitochondrial metabolism.

    doi.org/10.1055/s-0043-120065

    academia
    organ/tissue, human, clinical, diabetes
  68. Journal of Cell Science, 2017

    68Iron affects Ire1 clustering propensity and the amplitude of endoplasmic reticulum stress signaling

    Nir Cohen, Michal Breker, Anush Bakunts, Kristina Pesek, Ainara Chas, Josepmaria Argemí, Andrea Orsi, Lihi Gal, Silvia Chuartzman, Yoav Wigelman, Felix Jonas, Peter Walter, Robert Ernst, Tomás Aragón, Eelco van Anken, Maya Schuldiner

    Abstract

    The unfolded protein response (UPR) allows cells to adjust secretory pathway capacity according to need. Ire1, the endoplasmic reticulum (ER) stress sensor and central activator of the UPR is conserved from the budding yeast Saccharomyces cerevisiae to humans. Under ER stress conditions, Ire1 clusters into foci that enable optimal UPR activation. To discover factors that affect Ire1 clustering, we performed a high-content screen using a whole-genome yeast mutant library expressing Ire1–mCherry. We imaged the strains following UPR induction and found 154 strains that displayed alterations in Ire1 clustering. The hits were enriched for iron and heme effectors and binding proteins. By performing pharmacological depletion and repletion, we confirmed that iron (Fe3+) affects UPR activation in both yeast and human cells. We suggest that Ire1 clustering propensity depends on membrane composition, which is governed by heme-dependent biosynthesis of sterols. Our findings highlight the diverse cellular functions that feed into the UPR and emphasize the cross-talk between organelles required to concertedly maintain homeostasis.

    doi.org/10.1242/jcs.201715

    academia
    cells, yeast, basic science
  69. Biophysical Journal, 2017

    69Miscibility Transition Temperature Scales with Growth Temperature in a Zebrafish Cell Line

    Margaret Burns, Kathleen Wisser, Jing Wu, Ilya Levental, Sarah L Veatch

    Abstract

    Cells can alter the lipid content of their plasma membranes upon changes in their environment to maintain and adjust membrane function. Recent work suggests that some membrane functions arise because cellular plasma membranes are poised close to a miscibility transition under growth conditions. Here we report experiments utilizing giant plasma membrane vesicles (GPMVs) to explore how membrane transition temperature varies with growth temperature in a zebrafish cell line (ZF4) that can be adapted for growth between 20 and 32°C. We find that GPMV transition temperatures adjust to be 16.7 +/- 1.2°C below growth temperature for four growth temperatures investigated and that adjustment occurs over roughly 2 days when temperature is abruptly lowered from 28 to 20°C. We also find that GPMVs have slightly different lipidomes when isolated from cells adapted for growth at 28 and 20°C. Similar to past work in vesicles derived from mammalian cells, fluctuating domains are observed in ZF4-derived GPMVs, consistent with their having critical membrane compositions. Taken together, these experimental results suggest that cells in culture biologically tune their membrane composition in a way that maintains specific proximity to a critical miscibility transition.

    doi.org/10.1016/j.bpj.2017.04.052

    academia
    zebrafish, organelle, basic science
  70. Molecular Metabolism, 2017

    70The Munich MIDY Pig Biobank – A unique resource for studying organ crosstalk in diabetes

    Andreas Blutke, Simone Renner, Florian Flenkenthaler, Mattias Backman, Serena Haesner, Elisabeth Kemter, Erik Ländström, Christina Braun-Reichhart, Barbara Albl, Elisabeth Streckel, Birgit Rathkolb, Cornelia Prehn, Alessandra Palladini, Michal Grzybek, Stefan Krebs, Stefan Bauersachs, Andrea Bähr, Andreas Brühschwein, Cornelia A Deeg, Erica De Monte, Michaela Dmochewitz, Caroline Eberle, Daniela Emrich, Robert Fux, Frauke Groth, Sophie Gumbert, Antonia Heitmann, Arne Hinrichs, Barbara Keßler, Mayuko Kurome, Miriam Leipig-Rudolph, Kaspar Matiasek, Horst D Reichenbach, Hazal Öztürk, Christiane Otzdorff, Myriam Reichenbach, Alexandra Rieger, Birte Rieseberg, Marco Rosati, Manuel N Saucedo, Anna Schleicher, Marlon R Schneider, Kilian Simmet, Judith Steinmetz, Nicole Übel, Patrizia Zehetmaier, Andreas Jung, Jerzy Adamski, Ünal Coskun, Martin Hrabe de Angelis, Christian Simmet, Mathias Ritzmann, Andrea Meyer-Lindenberg, Helmut Blum, Georg J Arnold, Thomas Fröhlich, Rüdiger Wanke, Eckhard Wolf

    Abstract

    The prevalence of diabetes mellitus and associated complications is steadily increasing. As a resource for studying systemic consequences of chronic insulin insufficiency and hyperglycemia, we established a comprehensive biobank of long-term diabetic INSC94Y transgenic pigs, a model of mutant INS gene-induced diabetes of youth (MIDY), and of wild-type (WT) littermates.

    Female MIDY pigs (n = 4) were maintained with suboptimal insulin treatment for 2 years, together with female WT littermates (n = 5). Plasma insulin, C-peptide and glucagon levels were regularly determined using specific immunoassays. In addition, clinical chemical, targeted metabolomics, and lipidomics analyses were performed. At age 2 years, all pigs were euthanized, necropsied, and a broad spectrum of tissues was taken by systematic uniform random sampling procedures. Total beta cell volume was determined by stereological methods. A pilot proteome analysis of pancreas, liver, and kidney cortex was performed by label free proteomics.

    MIDY pigs had elevated fasting plasma glucose and fructosamine concentrations, C-peptide levels that decreased with age and were undetectable at 2 years, and an 82% reduced total beta cell volume compared to WT. Plasma glucagon and beta hydroxybutyrate levels of MIDY pigs were chronically elevated, reflecting hallmarks of poorly controlled diabetes in humans. In total, ∼1900 samples of different body fluids (blood, serum, plasma, urine, cerebrospinal fluid, and synovial fluid) as well as ∼17,000 samples from ∼50 different tissues and organs were preserved to facilitate a plethora of morphological and molecular analyses. Principal component analyses of plasma targeted metabolomics and lipidomics data and of proteome profiles from pancreas, liver, and kidney cortex clearly separated MIDY and WT samples.

    The broad spectrum of well-defined biosamples in the Munich MIDY Pig Biobank that will be available to the scientific community provides a unique resource for systematic studies of organ crosstalk in diabetes in a multi-organ, multi-omics dimension.

    doi.org/10.1016/j.molmet.2017.06.004

    academia
    plasma/serum, diabetes, other mammals
  71. The FASEB Journal, 2017

    71Lipin-1 regulation of phospholipid synthesis maintains endoplasmic reticulum homeostasis and is critical for triple-negative breast cancer cell survival

    Jingquan He, Feng Zhang, Li W R Tay, Salome Boroda, Weiqi Nian, Kandice R Levental, Ilya Levental, Thurl E Harris, Jeffrey T Chang, Guangwei Du

    Abstract

    Cancer cells reprogram their metabolism to increase the synthesis of macromolecules for rapid proliferation. Compared to fatty acids, much less is known about the synthesis of phospholipids, which is essential for membrane biogenesis in cancer cells. We found that LPIN1, which encodes lipin-1, a phosphatidic acid phosphatase (PAP) controlling the rate-limiting step in the phospholipid synthesis pathway, is highly up-regulated in basal-like triple-negative breast cancer (TNBC). Moreover, high LPIN1 expression correlates with the poor prognosis of these patients. Knockdown of LPIN1 increases apoptosis in basal-like TNBC cell lines, whereas it has minimal or less effect on normal human mammary gland epithelial cells (HMECs) and estrogen receptor-positive breast cancer cell lines. Fatty acid incorporation and lipidomics analyses showed that LPIN1 knockdown blocks phospholipid synthesis and changes membrane lipid compositions that ultimately induce the activation of 1 of the 3 branches of unfolded protein responses, the inositol-requiring enzyme-1α pathway. We also show for the first time, to our knowledge, that lipin-1 knockdown significantly inhibits tumor growth in vivo using an orthotopic xenograft breast mouse model. Our results suggest that lipin-1 is a potential target for cancer therapy.

    doi.org/10.1096/fj.201601353R

    academia
    human, cells, cancer
  72. White Paper Series, 2017

    72Big Data Lipidomics

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

    Abstract

    Lipidomics is the large-scale study of lipids in biological systems. The analysis of large datasets, potentially containing up to thousands of lipidomes, is a challenging endeavour. We have established multiparametric statistical approaches, tailored to quantify lipid data. These methods are geared to identify lipid biomarkers. In this white paper a cohort of healthy subjects is compared with a cohort of diseased persons to identify lipid signatures that discriminate health from disease. Such signatures could potentially be useful for disease stratification or for diagnosis by means of predictive modelling (machine learning).

    In this white paper, we will guide you through the data analysis process aiming at the identification of lipid biomarkers and the evaluations of their performance.

    www.lipotype.com/big-data-lipidomics/

    white papers
    human, biomarker, plasma/serum, method
  73. Scientific Reports, 2017

    73Heritability and responses to high fat diet of plasma lipidomics in a twin study

    Turid Frahnow, Martin A Osterhoff, Silke Hornemann, Michael Kruse, Michal A Surma, Christian Klose, Kai Simons, Andreas F H Pfeiffer

    Abstract

    Lipidomics have a great potential as clinical tool for monitoring metabolic changes in health and disease. Nevertheless hardly anything is known about the heritability of lipids. Therefore, it is necessary to clarify how and how much we can affect these progresses in individuals. In our interventional twin study (46 healthy, non-obese twin pairs) we investigated the lipid profile in plasma samples after switching from a low fat diet to an isocaloric high fat diet (HFD) to characterize the metabolic adaptation. Additionally we used the ACE model for Additive genetics, Common and unique Environment as well as linear mixed modelling to analyse the heritability of lipids. The heritability of lipids varied between 0–62% and applied to lipid species rather than to lipid classes. Phospholipids showed the highest inheritance. In addition, sex, body mass index (BMI) and age were important modifiers. The lipid profile changed already after one week of HFD and diverged further after 5 weeks of additional HFD. Basal concentrations of specific lipids within phospholipids are strongly inherited and are likely to be associated with heritable disease risks. BMI, sex and age were major modifiers. Nutrition strongly alters specific lipid classes, and has to be controlled in clinical association studies.

    doi.org/10.1038/s41598-017-03965-6

    academia
    clinical, human, diet, plasma/serum
  74. The Pharmacogenomics Journal, 2017

    74Urinary Lipidomics: evidence for multiple sources and sexual dimorphism in healthy individuals

    Juergen Graessler, Carola S Mehnert, Klaus-Martin Schulte, Sybille Bergmann, S Strauss, Tobias D Bornstein, Julio Licinio, Ma-Li Wong, Andreas L Birkenfeld, Stefan R Bornstein

    Abstract

    Urinary lipidomics may add new valuable biomarkers to the diagnostic armamentarium for early detection of metabolic and kidney diseases. Sources and composition of urinary lipids in healthy individuals, however, have not been investigated in detail. Shotgun lipidomics was used to quantify lipidomic profiles in native urine samples from 16 individuals (eight men, eight women) collected in five fractions over 24 h. All probands were comprehensively characterized by urinary and clinical indices. The mean total urinary lipid concentration per sample was 0.84 μM in men and 1.03 μM in women. We observed significant intra- and interindividual variations of lipid concentrations over time, but failed to detect a clear circadian pattern. Based on quantity and subclass composition it seems very unlikely that plasma serves as major source for the urinary lipidome. Considering lipid metabolites occurring in at least 20% of all samples 38 lipid species from 7 lipid classes were identified. Four phosphatidylserine and one phosphatidylethanolamine ether species (PE-O 36:5) were detectable in almost all urine samples. Sexual dimorphism has been found mainly for phosphatidylcholines and phosphatidylethanolamines. In men and in women urinary lipid species were highly correlated with urinary creatinine and albumin excretion, reflecting glomerular filtration and tubular transport processes. In women, however, lipid species deriving from urinary cells and cellular constituents of the lower genitourinary tract considerably contributed to the urinary lipidome. In conclusion, our study revealed the potential of urinary lipidomics but also the complexity of methodological challenges which have to be overcome for its implementation as a routine diagnostic tool for renal, urological and metabolic diseases.

    doi.org/10.1038/tpj.2017.24

    academia
    urine, clinical, human, biomarker
  75. Patent, 2017

    75Methods and compositions of chondrisomes

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

    Abstract

    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. bioenergetic or biological function, for use in therapeutic applications.

    freepatentsonline.com/y2017/0151287.html

    industry
    organelle, pharma, method
  76. Scientific Reports, 2017

    76Enlightening discriminative network functional modules behind Principal Component Analysis separation in differential-omic science studies

    Sara Ciucci, Yan Ge, Claudio Durán, Alessandra Palladini, Víctor Jiménez-Jiménez, Luisa M Martínez-Sánchez, Yuting Wang, Susanne Sales, Andrej Shevchenko, Steven W Poser, Maik Herbig, Oliver Otto, Andreas Androutsellis-Theotokis, Jochen Guck, Mathias J Gerl, Carlo V Cannistraci

    Abstract

    Omic science is rapidly growing and one of the most employed techniques to explore differential patterns in omic datasets is principal component analysis (PCA). However, a method to enlighten the network of omic features that mostly contribute to the sample separation obtained by PCA is missing. An alternative is to build correlation networks between univariately-selected significant omic features, but this neglects the multivariate unsupervised feature compression responsible for the PCA sample segregation. Biologists and medical researchers often prefer effective methods that offer an immediate interpretation to complicated algorithms that in principle promise an improvement but in practice are difficult to be applied and interpreted. Here we present PC-corr: a simple algorithm that associates to any PCA segregation a discriminative network of features. Such network can be inspected in search of functional modules useful in the definition of combinatorial and multiscale biomarkers from multifaceted omic data in systems and precision biomedicine. We offer proofs of PC-corr efficacy on lipidomic, metagenomic, developmental genomic, population genetic, cancer promoteromic and cancer stem-cell mechanomic data. Finally, PC-corr is a general functional network inference approach that can be easily adopted for big data exploration in computer science and analysis of complex systems in physics.

    doi.org/10.1038/srep43946

    academia
    software, method
  77. Whitepaper Series, 2017

    77Skin Lipidomics

    Tomasz Sadowski, Christian Klose, Mathias J Gerl, Anna Wójcik-Maciejewicz, Ronny Herzog, Kai Simons, Adam Reich, Michal A Surma

    Abstract

    The lipid composition of human skin is essential for its function. However, the simultaneous quantification of a wide range of stratum corneum and sebaceous lipids is not trivial. We developed and validated a quantitative high-throughput shotgun mass spectrometry-based platform for lipid analysis of tape-stripped skin samples. Lipotype analyzes also other types of skin samples, from monolayers to 3D models. It is now easy to investigate how the healthy skin lipidome is composed, how it changes in diseases or upon intervention with a drug or a cosmetic product. This lipidomic data can be used for cosmetic claim support, topical drug development and personalized cosmetics.

    www.lipotype.com/lipotype-skin-lipidomics/

    white papers
    cosmetics, human, skin, method
  78. Scientific Reports, 2017

    78Large-scale human skin lipidomics by quantitative, high-throughput shotgun mass spectrometry

    Tomasz Sadowski, Christian Klose, Mathias J Gerl, Anna Wójcik-Maciejewicz, Ronny Herzog, Kai Simons, Adam Reich, Michal A Surma

    Abstract

    The lipid composition of human skin is essential for its function; however the simultaneous quantification of a wide range of stratum corneum (SC) and sebaceous lipids is not trivial. We developed and validated a quantitative high-throughput shotgun mass spectrometry-based platform for lipid analysis of tape-stripped SC skin samples. It features coverage of 16 lipid classes; total quantification to the level of individual lipid molecules; high reproducibility and high-throughput capabilities. With this method we conducted a large lipidomic survey of 268 human SC samples, where we investigated the relationship between sampling depth and lipid composition, lipidome variability in samples from 14 different sampling sites on the human body and finally, we assessed the impact of age and sex on lipidome variability in 104 healthy subjects. We found sebaceous lipids to constitute an abundant component of the SC lipidome as they diffuse into the topmost SC layers forming a gradient. Lipidomic variability with respect to sampling depth, site and subject is considerable, and mainly accredited to sebaceous lipids, while stratum corneum lipids vary less. This stresses the importance of sampling design and the role of sebaceous lipids in skin studies.

    doi.org/10.1038/srep43761

    academia
    cosmetics, human, skin, method
  79. PLOS ONE, 2017

    79Lipidomic approach for stratification of acute myeloid leukemia patients

    Adam Stefanko, Christian Thiede, Gerhard Ehninger, Kai Simons, Michal Grzybek

    Abstract

    The pathogenesis and progression of many tumors, including hematologic malignancies is highly dependent on enhanced lipogenesis. De novo fatty-acid synthesis permits accelerated proliferation of tumor cells by providing membrane components but these may also alter physicochemical properties of lipid bilayers, which can impact signaling or even increase drug resistance in cancer cells. Cancer type-specific lipid profiles would permit us to monitor and interpret actual effects of lipid changes, potential fingerprints of individual tumors to be explored as diagnostic markers. We have used the shotgun MS approach to identify lipid patterns in different types of acute myeloid leukemia (AML) patients that either show no karyotype change or belong to t(8;21) or inv16 types. Differences in lipidomes of t(8;21) and inv(16) patients, as compared to AML patients without karyotype change, presented mostly as substantial modulation of ceramide/sphingolipid synthesis. Furthermore, between the t(8;21) and all other patients we observed significant changes in physicochemical membrane properties. These were related to a marked alteration in lipid saturation levels. The discovered differences in lipid profiles of various AML types improve our understanding of the pathobiochemical pathways involved and may serve in the development of diagnostic tools.

    doi.org/10.1371/journal.pone.0168781

    academia
    human, clinical, biomarker, cells, cancer
  80. Scientific Reports, 2017

    80A novel approach to analyze lysosomal dysfunctions through subcellular proteomics and lipidomics: the case of NPC1 deficiency

    Arun K Tharkeshwar, Jesse Trekker, Wendy Vermeire, Jarne Pauwels, Ragna Sannerud, David A Priestman, Danielle te Vruchte, Katlijn Vints, Pieter Baatsen, Jean-Paul Decuypere, Huiqi Lu, Shaun Martin, Peter Vangheluwe, Johannes V Swinnen, Liesbet Lagae, Francis Impens, Frances M Platt, Kris Gevaert, Wim Annaert

    Abstract

    Superparamagnetic iron oxide nanoparticles (SPIONs) have mainly been used as cellular carriers for genes and therapeutic products, while their use in subcellular organelle isolation remains underexploited. We engineered SPIONs targeting distinct subcellular compartments. Dimercaptosuccinic acid-coated SPIONs are internalized and accumulate in late endosomes/lysosomes, while aminolipid-SPIONs reside at the plasma membrane. These features allowed us to establish standardized magnetic isolation procedures for these membrane compartments with a yield and purity permitting proteomic and lipidomic profiling. We validated our approach by comparing the biomolecular compositions of lysosomes and plasma membranes isolated from wild-type and Niemann-Pick disease type C1 (NPC1) deficient cells. While the accumulation of cholesterol and glycosphingolipids is seen as a primary hallmark of NPC1 deficiency, our lipidomics analysis revealed the buildup of several species of glycerophospholipids and other storage lipids in selectively late endosomes/lysosomes of NPC1-KO cells. While the plasma membrane proteome remained largely invariable, we observed pronounced alterations in several proteins linked to autophagy and lysosomal catabolism reflecting vesicular transport obstruction and defective lysosomal turnover resulting from NPC1 deficiency. Thus the use of SPIONs provides a major advancement in fingerprinting subcellular compartments, with an increased potential to identify disease-related alterations in their biomolecular compositions.

    doi.org/10.1038/srep41408

    academia
    human, cells, organelle, basic science
  81. Journal of Cell Biology, 2017

    81Cardiolipin promotes electron transport between ubiquinone and complex I to rescue PINK1 deficiency

    Melissa Vos, Ann Geens, Claudia Böhm, Liesbeth Deaulmerie, Jef Swerts, Matteo Rossi, Katleen Craessaerts, Elvira P Leites, Philip Seibler, Aleksandar Rakovic, Thora Lohnau, Bart De Strooper, Sarah-Maria Fendt, Vanessa A Morais, Christine Klein, Patrik Verstreken

    Abstract

    PINK1 is mutated in Parkinson’s disease (PD), and mutations cause mitochondrial defects that include inefficient electron transport between complex I and ubiquinone. Neurodegeneration is also connected to changes in lipid homeostasis, but how these are related to PINK1-induced mitochondrial dysfunction is unknown. Based on an unbiased genetic screen, we found that partial genetic and pharmacological inhibition of fatty acid synthase (FASN) suppresses toxicity induced by PINK1 deficiency in flies, mouse cells, patient-derived fibroblasts, and induced pluripotent stem cell–derived dopaminergic neurons. Lower FASN activity in PINK1 mutants decreases palmitate levels and increases the levels of cardiolipin (CL), a mitochondrial inner membrane–specific lipid. Direct supplementation of CL to isolated mitochondria not only rescues the PINK1-induced complex I defects but also rescues the inefficient electron transfer between complex I and ubiquinone in specific mutants. Our data indicate that genetic or pharmacologic inhibition of FASN to increase CL levels bypasses the enzymatic defects at complex I in a PD model.

    doi.org/10.1083/jcb.201511044

    academia
    mouse, organelle, pharma, neuro
  82. Cell, 2016

    82Lipid-Sorting Specificity Encoded in K-Ras Membrane Anchor Regulates Signal Output

    Yong Zhou, Priyanka Prakash, Hong Liang, Kwang-Jin Cho, Alemayehu A Gorfe, John F Hancock

    Abstract

    K-Ras is targeted to the plasma membrane by a C-terminal membrane anchor that comprises a farnesyl-cysteine-methyl-ester and a polybasic domain. We used quantitative spatial imaging and atomistic molecular dynamics simulations to examine molecular details of K-Ras plasma membrane binding. We found that the K-Ras anchor binds selected plasma membrane anionic lipids with defined head groups and lipid side chains. The precise amino acid sequence and prenyl group define a combinatorial code for lipid binding that extends beyond simple electrostatics; within this code lysine and arginine residues are non-equivalent and prenyl chain length modifies nascent polybasic domain lipid preferences. The code is realized by distinct dynamic tertiary structures of the anchor on the plasma membrane that govern amino acid side-chain-lipid interactions. An important consequence of this specificity is the ability of such anchors when aggregated to sort subsets of phospholipids into nanoclusters with defined lipid compositions that determine K-Ras signaling output.

    doi.org/10.1016/j.cell.2016.11.059

    academia
    cells, other mammals, basic science
  83. Molecular Biology of the Cell, 2016

    83Dissecting Torsin/cofactor function at the nuclear envelope: a genetic study

    Ethan Laudermilch, Pei-Ling Tsai, Morven Graham, Elizabeth Turner, Chenguang Zhao, Christian Schlieker

    Abstract

    The human genome encodes four Torsin ATPases, the functions of which are poorly understood. In this study, we use CRISPR/Cas9 engineering to delete all four Torsin ATPases individually and in combination. Using nuclear envelope (NE) blebbing as a phenotypic measure, we establish a direct correlation between the number of inactivated Torsin alleles and the occurrence of omega-shaped herniations within the lumen of the NE. A similar, although not identical, redundancy is observed for LAP1 and LULL1, which serve as regulatory cofactors for a subset of Torsin ATPases. Unexpectedly, deletion of Tor2A in a TorA/B/3A-deficient background results in a stark increase of bleb formation, even though Tor2A does not respond to LAP1/LULL1 stimulation. The robustness of the observed phenotype in Torsin-deficient cells enables a structural analysis via electron microscopy tomography and a compositional analysis via immunogold labeling. Ubiquitin and nucleoporins were identified as distinctively localizing components of the omega-shaped bleb structure. These findings suggest a functional link between the Torsin/cofactor system and NE/nuclear pore complex biogenesis or homeostasis and establish a Torsin-deficient cell line as a valuable experimental platform with which to decipher Torsin function.

    doi.org/10.1091/mbc.E16-07-0511

    academia
    human, organelle, basic science
  84. Journal of the AHA, 2016

    84Identification of Shared and Unique Serum Lipid Profiles in Diabetes Mellitus and Myocardial Infarction

    Sanela Kjellqvist, Christian Klose, Michal A Surma, Geroge Hindy, Ines G Mollet, Anna Johansson, Patrick Chavaux, Johan Gottfries, Kai Simons, Olle Melander, Céline Fernandez

    Abstract

    Diabetes mellitus (DM) and cardiovascular disease are associated with dyslipidemia, but the detailed lipid molecular pattern in both diseases remains unknown.

    We used shotgun mass spectrometry to determine serum levels of 255 molecular lipids in 316 controls, 171 DM, and 99 myocardial infarction (MI) events from a cohort derived from the Malmö Diet and Cancer study. Orthogonal projections to latent structures analyses were conducted between the lipids and clinical parameters describing DM or MI. Fatty acid desaturases (FADS) and elongation of very long chain fatty acid protein 5 (ELOVL5) activities were estimated by calculating product to precursor ratios of polyunsaturated fatty acids in complex lipids. FADS genotypes encoding these desaturases were then tested for association with lipid levels and ratios. Differences in the levels of lipids belonging to the phosphatidylcholine and triacylglyceride (TAG) classes contributed the most to separating DM from controls. TAGs also played a dominating role in discriminating MI from controls. Levels of C18:2 fatty acids in complex lipids were lower both in DM and MI versus controls (DM, P=0.004; MI, P=6.0E‐06) at least due to an acceleration in the metabolic flux from C18:2 to C20:4 (eg, increased estimated ELOVL5: DM, P=0.02; MI, P=0.04, and combined elongase‐desaturase activities: DM, P=3.0E‐06; MI, P=2.0E‐06). Minor allele carriers of FADS genotypes were associated with increased levels of C18:2 (P≤0.007) and lower desaturase activity (P≤0.002).

    We demonstrate a possible relationship between decreased levels of C18:2 in complex lipids and DM or MI. We thereby highlight the importance of molecular lipids in the pathogenesis of both diseases.

    doi.org/10.1161/JAHA.116.004503

    academia
    human, biomarker, plasma/serum, diabetes, CVD
  85. The Journal of Physical Chemistry B, 2016

    85Domain Stability in Biomimetic Membranes Driven by Lipid Polyunsaturation

    Xubo Lin, Joseph H Lorent, Allison D Skinkle, Kandice R Levental, M Neal Waxham, Alemayehu A Gorfe, Ilya Levental

    Abstract

    Biological membranes contain a broad variety of lipid species whose individual physicochemical properties and collective interactions ultimately determine membrane organization. A key aspect of the organization of cellular membranes is their lateral subdivision into domains of distinct structure and composition. The most widely studied membrane domains are lipid rafts, which are the biological manifestations of liquid-ordered phases that form in sterol-containing membranes. Detailed studies of biomimetic membrane mixtures have yielded wide-ranging insights into the physical principles behind lipid rafts; however, these simplified models do not fully capture the diversity and complexity of the mammalian lipidome, most notably in their exclusion of polyunsaturated lipids. Here, we assess the role of lipid acyl chain unsaturation as a driving force for phase separation using coarse-grained molecular dynamics (CGMD) simulations validated by model membrane experiments. The clear trends in our observations and good qualitative agreements between simulations and experiments support the conclusions that highly unsaturated lipids promote liquid–liquid domain stability by enhancing the differences in cholesterol content and lipid chain order between the coexisting domains. These observations reveal the important role of noncanonical biological lipids in the physical properties of membranes, showing that lipid polyunsaturation is a driving force for liquid–liquid phase separation.

    doi.org/10.1021/acs.jpcb.6b06815

    academia
    organelle, other mammals, basic science
  86. Oncotarget, 2016

    86The anti-tumor drug 2-hydroxyoleic acid (Minerval) stimulates signaling and retrograde transport

    Maria L Torgersen, Tove I Klokk, Simona Kavaliauskiene, Christian Klose, Kai Simons, Tore Skotland, Kirsten Sandvig

    Abstract

    2-hydroxyoleic acid (OHOA, Minerval®) is an example of a substance used for membrane lipid therapy, where the cellular membranes rather than specific proteins constitute the therapeutical target. OHOA is thought to mediate its anti-tumor effect by affecting the biophysical properties of membranes, which leads to altered recruitment and activation of amphitropic proteins, altered cellular signaling, and eventual cell death. Little is known about the initial signaling events upon treatment with OHOA, and whether the altered membrane properties would have any impact on the dynamic intracellular transport system. In the present study we demonstrate that treatment with OHOA led to a rapid release of intracellular calcium and activation of multiple signaling pathways in HeLa cells, including the PI3K-AKT1-MTOR pathway and several MAP kinases, in a process independent of the EGFR. By lipidomics we confirmed that OHOA was incorporated into several lipid classes. Concomitantly, OHOA potently increased retrograde transport of the plant toxin ricin from endosomes to the Golgi and further to the endoplasmic reticulum. The OHOA-stimulated ricin transport seemed to require several amphitropic proteins, including Src, phospholipase C, protein kinase C, and also Ca2+/calmodulin. Interestingly, OHOA induced a slight increase in endosomal localization of the retromer component VPS35. Thus, our data show that addition of a lipid known to alter membrane properties not only affects signaling, but also intracellular transport.

    doi.org/10.18632/oncotarget.13508

    academia
    human, cells, pharma, cancer
  87. Molecular Biology of the Cell, 2016

    87Remodeling of the postsynaptic plasma membrane during neural development

    Karolina Tulodziecka, Barbara B Diaz-Rohrer, Madeline M Farley, Robin B Chan, Gilbert Di Paolo, Kandice R Levental, M Neal Waxham, Ilya Levental

    Abstract

    Neuronal synapses are the fundamental units of neural signal transduction and must maintain exquisite signal fidelity while also accommodating the plasticity that underlies learning and development. To achieve these goals, the molecular composition and spatial organization of synaptic terminals must be tightly regulated; however, little is known about the regulation of lipid composition and organization in synaptic membranes. Here we quantify the comprehensive lipidome of rat synaptic membranes during postnatal development and observe dramatic developmental lipidomic remodeling during the first 60 postnatal days, including progressive accumulation of cholesterol, plasmalogens, and sphingolipids. Further analysis of membranes associated with isolated postsynaptic densities (PSDs) suggests the PSD-associated postsynaptic plasma membrane (PSD-PM) as one specific location of synaptic remodeling. We analyze the biophysical consequences of developmental remodeling in reconstituted synaptic membranes and observe remarkably stable microdomains, with the stability of domains increasing with developmental age. We rationalize the developmental accumulation of microdomain-forming lipids in synapses by proposing a mechanism by which palmitoylation of the immobilized scaffold protein PSD-95 nucleates domains at the postsynaptic plasma membrane. These results reveal developmental changes in lipid composition and palmitoylation that facilitate the formation of postsynaptic membrane microdomains, which may serve key roles in the function of the neuronal synapse.

    doi.org/10.1091/mbc.E16-06-0420

    academia
    organelle, neuro, other mammals
  88. Plant Physiology, 2016

    88Lack of FTSH4 Protease Affects Protein Carbonylation, Mitochondrial Morphology, and Phospholipid Content in Mitochondria of Arabidopsis: New Insights into a Complex Interplay

    Elwira Smakowska, Renata Skibior-Blaszczyk, Malgorzata Czarna, Marta Kolodziejczak, Malgorzata Kwasniak-Owczarek, Katarzyna Parys, Christiane Funk, Hanna Janska

    Abstract

    FTSH4 is one of the inner membrane-embedded ATP-dependent metalloproteases in mitochondria of Arabidopsis (Arabidopsis thaliana). In mutants impaired to express FTSH4, carbonylated proteins accumulated and leaf morphology was altered when grown under a short-day photoperiod, at 22°C, and a long-day photoperiod, at 30°C. To provide better insight into the function of FTSH4, we compared the mitochondrial proteomes and oxyproteomes of two ftsh4 mutants and wild-type plants grown under conditions inducing the phenotypic alterations. Numerous proteins from various submitochondrial compartments were observed to be carbonylated in the ftsh4 mutants, indicating a widespread oxidative stress. One of the reasons for the accumulation of carbonylated proteins in ftsh4 was the limited ATP-dependent proteolytic capacity of ftsh4 mitochondria, arising from insufficient ATP amount, probably as a result of an impaired oxidative phosphorylation (OXPHOS), especially complex V. In ftsh4, we further observed giant, spherical mitochondria coexisting among normal ones. Both effects, the increased number of abnormal mitochondria and the decreased stability/activity of the OXPHOS complexes, were probably caused by the lower amount of the mitochondrial membrane phospholipid cardiolipin. We postulate that the reduced cardiolipin content in ftsh4 mitochondria leads to perturbations within the OXPHOS complexes, generating more reactive oxygen species and less ATP, and to the deregulation of mitochondrial dynamics, causing in consequence the accumulation of oxidative damage.

    doi.org/10.1104/pp.16.00370

    academia
    organelle, plants, basic science
  89. Developmental Cell, 2016

    89Torsins Are Essential Regulators of Cellular Lipid Metabolism

    Micheline Grillet, Beatriz Dominguez Gonzalez, Adria Sicart, Maria Pöttler, Ana Cascalho, Karolien Billion, Sergio Hernandez Diaz, Jef Swerts, Teresa V Naismith, Natalia V Gounko, Patrik Verstreken, Phyllis I Hanson, Rose E Goodchild

    Abstract

    Torsins are developmentally essential AAA+ proteins, and mutation of human torsinA causes the neurological disease DYT1 dystonia. They localize in the ER membranes, but their cellular function remains unclear. We now show that dTorsin is required in Drosophila adipose tissue, where it suppresses triglyceride levels, promotes cell growth, and elevates membrane lipid content. We also see that human torsinA at the inner nuclear membrane is associated with membrane expansion and elevated cellular lipid content. Furthermore, the key lipid metabolizing enzyme, lipin, is mislocalized in dTorsin-KO cells, and dTorsin increases levels of the lipin substrate, phosphatidate, and reduces the product, diacylglycerol. Finally, genetic suppression of dLipin rescues dTorsin-KO defects, including adipose cell size, animal growth, and survival. These findings identify that torsins are essential regulators of cellular lipid metabolism and implicate disturbed lipid biology in childhood-onset DYT1 dystonia.

    doi.org/10.1016/j.devcel.2016.06.017

    academia
    organ/tissue, fly, neuro
  90. Biophysical Journal, 2016

    90Polyunsaturated Lipids Regulate Membrane Domain Stability by Tuning Membrane Order

    Kandice R Levental, Joseph H Lorent, Xubo Lin, Allison D Skinkle, Michal A Surma, Emily A Stockenbojer, Alemayehu A Gorfe, Ilya Levental

    Abstract

    The plasma membrane (PM) serves as the functional interface between a cell and its environment, hosting extracellular signal transduction and nutrient transport among a variety of other processes. To support this extensive functionality, PMs are organized into lateral domains, including ordered, lipid-driven assemblies termed lipid rafts. Although the general requirements for ordered domain formation are well established, how these domains are regulated by cell-endogenous mechanisms or exogenous perturbations has not been widely addressed. In this context, an intriguing possibility is that dietary fats can incorporate into membrane lipids to regulate the properties and physiology of raft domains. Here, we investigate the effects of polyunsaturated fats on the organization of membrane domains across a spectrum of membrane models, including computer simulations, synthetic lipid membranes, and intact PMs isolated from mammalian cells. We observe that the ω-3 polyunsaturated fatty acid docosahexaenoic acid is robustly incorporated into membrane lipids, and this incorporation leads to significant remodeling of the PM lipidome. Across model systems, docosahexaenoic acid-containing lipids enhance the stability of ordered raft domains by increasing the order difference between them and coexisting nonraft domains. The relationship between interdomain order disparity and the stability of phase separation holds for a spectrum of different perturbations, including manipulation of cholesterol levels and high concentrations of exogenous amphiphiles, suggesting it as a general feature of the organization of biological membranes. These results demonstrate that polyunsaturated fats affect the composition and organization of biological membranes, suggesting a potential mechanism for the extensive effects of dietary fat on health and disease.

    doi.org/10.1016/j.bpj.2016.03.012

    academia
    diet, organelle, other mammals, basic science
  91. Nature Cell Biology, 2016

    91Control of plasma membrane lipid homeostasis by the extended synaptotagmins

    Yasunori Saheki, Xin Bian, Curtis M Schauder, Yujin Sawaki, Michal A Surma, Christian Klose, Frederic Pincet, Karin M Reinisch, Pietro De Camilli

    Abstract

    Acute metabolic changes in plasma membrane (PM) lipids, such as those mediating signalling reactions, are rapidly compensated by homeostatic responses whose molecular basis is poorly understood. Here we show that the extended synaptotagmins (E-Syts), endoplasmic reticulum (ER) proteins that function as PtdIns(4,5)P2– and Ca2+-regulated tethers to the PM, participate in these responses. E-Syts transfer glycerolipids between bilayers in vitro, and this transfer requires Ca2+ and their lipid-harbouring SMP domain. Genome-edited cells lacking E-Syts do not exhibit abnormalities in the major glycerolipids at rest, but exhibit enhanced and sustained accumulation of PM diacylglycerol following PtdIns(4,5)P2 hydrolysis by PLC activation, which can be rescued by expression of E-Syt1, but not by mutant E-Syt1 lacking the SMP domain. The formation of E-Syt-dependent ER–PM tethers in response to stimuli that cleave PtdIns(4,5)P2 and elevate Ca2+ may help reverse accumulation of diacylglycerol in the PM by transferring it to the ER for metabolic recycling.

    doi.org/10.1038/ncb3339

    academia
    human, cells, organelle, basic science
  92. BBA Biomembranes, 2016

    92Glycosylphosphatidylinositol-anchored proteins: Membrane organization and transport

    Chiara Zurzolo, Kai Simons

    Abstract

    Glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs) are a class of membrane proteins containing a soluble protein attached by a conserved glycolipid anchor to the external leaflet of the plasma membrane. In polarized epithelial cells, GPI-APs are predominantly sorted to the apical surface in the trans-Golgi network (TGN) by clustering in sphingolipid- and cholesterol-dependent microdomains (or rafts), which have been proposed to act as apical sorting platforms. Recent data indicate that the mechanisms of GPI-AP sorting, occurring in the Golgi, control both the membrane transport of GPI-APs and their specific activity at the apical surface of fully polarized epithelial cells. Here, we discuss the most recent findings and the factors regulating apical sorting of GPI-APs at the Golgi in polarized epithelial cells. We also underline the differences in the plasma membrane organization of GPI-APs between polarized and non-polarized cells supporting the existence of various mechanisms that control GPI-AP organization in different cell types.

    doi.org/10.1016/j.bbamem.2015.12.018

    academia
    basic science
  93. BBA Biomembranes, 2016

    93Cell membranes: A subjective perspective

    Kai Simons

    Abstract

    Cell membranes have developed a tremendous complexity of lipids and proteins geared to perform the functions cells require. The lipids have for long remained in the background and are now regaining their role as important building blocks of cells. Their main function is to form the matrix of our cell membranes where they support a variety of functions essential for life. This 2-dimensional fluid matrix has evolved unexpected material properties that involve both lipid-lipid and lipid-protein interactions. This perspective is a short summary of the challenges that this field faces and discusses potential ways and means for coming to grips with the properties of this incredible fluid.

    doi.org/10.1016/j.bbamem.2016.01.023

    academia
    basic science
  94. Molecular and Cellular Biology, 2016

    94Inhibition of Acid Sphingomyelinase Depletes Cellular Phosphatidylserine and Mislocalizes K-Ras from the Plasma Membrane

    Kwang-Jin Cho, Dharini van der Hoeven, Yong Zhou, Masahi Maekawa, Xiaoping Ma, Wei Chen, Gregory D Fairn, John F Hancock

    Abstract

    K-Ras must localize to the plasma membrane for biological activity; thus, preventing plasma membrane interaction blocks K-Ras signal output. Here we show that inhibition of acid sphingomyelinase (ASM) mislocalizes both the K-Ras isoforms K-Ras4A and K-Ras4B from the plasma membrane to the endomembrane and inhibits their nanoclustering. We found that fendiline, a potent ASM inhibitor, reduces the phosphatidylserine (PtdSer) and cholesterol content of the inner plasma membrane. These lipid changes are causative because supplementation of fendiline-treated cells with exogenous PtdSer rapidly restores K-Ras4A and K-Ras4B plasma membrane binding, nanoclustering, and signal output. Conversely, supplementation with exogenous cholesterol restores K-Ras4A but not K-Ras4B nanoclustering. These experiments reveal different operational pools of PtdSer on the plasma membrane. Inhibition of ASM elevates cellular sphingomyelin and reduces cellular ceramide levels. Concordantly, delivery of recombinant ASM or exogenous ceramide to fendiline-treated cells rapidly relocalizes K-Ras4B and PtdSer to the plasma membrane. K-Ras4B mislocalization is also recapitulated in ASM-deficient Neimann-Pick type A and B fibroblasts. This study identifies sphingomyelin metabolism as an indirect regulator of K-Ras4A and K-Ras4B signaling through the control of PtdSer plasma membrane content. It also demonstrates the critical and selective importance of PtdSer to K-Ras4A and K-Ras4B plasma membrane binding and nanoscale spatial organization.

    doi.org/10.1128/MCB.00719-15

    academia
    organelle, other mammals, basic science
  95. European Journal of Lipid Science and Technology, 2015

    95An automated shotgun lipidomics platform for high throughput, comprehensive, and quantitative analysis of blood plasma intact lipids

    Michal A Surma, Ronny Herzog, Andrej Vasilj, Christian Klose, Nicolas Christinat, Delphine Morin‐Rivron, Kai Simons, Mojgan Masoodi, Júlio L Sampaio

    Abstract

    Blood plasma has gained protagonism in lipidomics studies due to its availability, uncomplicated collection and preparation, and informative readout of physiological status. At the same time, it is also technically challenging to analyze due to its complex lipid composition affected by many factors, which can hamper the throughput and/or lipidomics coverage. To tackle these issues, we developed a comprehensive, high throughput, and quantitative mass spectrometry‐based shotgun lipidomics platform for blood plasma lipid analyses. The main hallmarks of this technology are (i) it is comprehensive, covering 22 quantifiable different lipid classes encompassing more than 200 lipid species; (ii) it is amenable to high‐throughput, with less than 5 min acquisition time allowing the complete analysis of 200 plasma samples per day; (iii) it achieves absolute quantification, by inclusion of internal standards for every lipid class measured; (iv) it is highly reproducible, achieving an average coefficient of variation of <10% (intra‐day), approx. 10% (inter‐day), and approx. 15% (inter‐site) for most lipid species; (v) it is easily transferable allowing the direct comparison of data acquired in different sites. Moreover, we thoroughly assessed the influence of blood stabilization with different anticoagulants and freeze‐thaw cycles to exclude artifacts generated by sample preparation.

    doi.org/10.1002/ejlt.201500145

    academia
    human, plasma/serum, method
  96. Product development, 2014

    96Lipid analysis of microorganisms for production of ingredients for the food, beverage and consumer health sectors

    Abstract

    Evolva has a proprietary, fermentation-based platform that allows radically different approaches to the production of ingredients for the food, beverage and consumer health sectors. As a pioneer and global leader in sustainable, fermentation-based approaches to ingredients, Evolva was interested in the quantitative analysis of the lipid composition of yeast cells and detailed information on the structural and quantitative lipid composition of yeast cells. The information on the lipid composition facilitated strain optimization and adjustments of culture conditions to ensure maximal production efficiency for the compound in question.

    www.lipotype.com/2014/10/evolva/

    industry
    cells, diet, yeast
  97. Analytical Chemistry, 2014

    97Systematic Screening for Novel Lipids by Shotgun Lipidomics

    Cyrus Papan, Sider Penkov, Ronny Herzog, Christoph Thiele, Teymuras Kurzchalia, Andrej Shevchenko

    Abstract

    A commonly accepted LIPID MAPS classification recognizes eight major lipid categories and over 550 classes, while new lipid classes are still being discovered by targeted biochemical approaches. Despite their compositional diversity, complex lipids such as glycerolipids, glycerophospholipids, saccharolipids, etc. are constructed from unique structural moieties, e.g., glycerol, fatty acids, choline, phosphate, and trehalose, that are linked by amide, ether, ester, or glycosidic bonds. This modular organization is also reflected in their MS/MS fragmentation pathways, such that common building blocks in different lipid classes tend to generate common fragments. We take advantage of this stereotyped fragmentation to systematically screen for new lipids sharing distant structural similarity to known lipid classes and have developed a discovery approach based on the computational querying of shotgun mass spectra by LipidXplorer software. We applied this concept for screening lipid extracts of C. elegans larvae at the dauer and L3 stages that represent alternative developmental programs executed in response to environmental challenges. The search, covering more than 1.5 million putative chemical compositions, identified a novel class of lyso-maradolipids specifically enriched in dauer larvae.

    doi.org/10.1021/ac404083u

    academia
    software, C elegans, cells, yeast
  98. Current Protocols in Bioinformatics, 2013

    98LipidXplorer: Software for Quantitative Shotgun Lipidomics Compatible with Multiple Mass Spectrometry Platforms

    Ronny Herzog, Dominik Schwudke, Andrej Shevchenko

    Abstract

    LipidXplorer is an open-source software kit that supports the identification and quantification of molecular species of any lipid class detected by shotgun experiments performed on any mass spectrometry platform. LipidXplorer does not rely on a database of reference spectra: instead, lipid identification routines are user defined in the declarative molecular fragmentation query language (MFQL). The software supports batch processing of multiple shotgun acquisitions by high-resolution mass mapping, precursor and neutral-loss scanning, and data-dependent MS/MS lending itself to a variety of lipidomics applications in cell biology and molecular medicine.

    doi.org/10.1002/0471250953.bi1412s43

    academia
    software
  99. Current Opinion in Cell Biology, 2013

    99Organellar lipidomics: background and perspectives

    Christian Klose, Michal A Surma, Kai Simons

    Abstract

    The basic structural units of eukaryotic cells are membrane-bound organelles and many essential cellular processes take place in and on membranes. It is becoming increasingly clear that these processes are influenced by the biophysical properties of the organelle membranes, which in turn are affected by their lipid composition. Even subtle changes in lipid composition can have a tremendous impact on membrane properties and the processes occurring within them. Therefore, in order to understand the contribution of membrane lipid composition to the functionality of membrane-bound cellular processes, comprehensive structural and quantitative information on the organellar lipidome is essential. Here we argue that only mass spectrometry-based organellar lipidomics can provide this information today.

    doi.org/10.1016/j.ceb.2013.03.005

    academia
    method
  100. PLOS ONE, 2012

    100Flexibility of a Eukaryotic Lipidome – Insights from Yeast Lipidomics

    Christian Klose, Michal A Surma, Mathias J Gerl, Felix Meyenhofer, Andrej Shevchenko, Kai Simons

    Abstract

    Mass spectrometry-based shotgun lipidomics has enabled the quantitative and comprehensive assessment of cellular lipid compositions. The yeast Saccharomyces cerevisiae has proven to be a particularly valuable experimental system for studying lipid-related cellular processes. Here, by applying our shotgun lipidomics platform, we investigated the influence of a variety of commonly used growth conditions on the yeast lipidome, including glycerophospholipids, triglycerides, ergosterol as well as complex sphingolipids. This extensive dataset allowed for a quantitative description of the intrinsic flexibility of a eukaryotic lipidome, thereby providing new insights into the adjustments of lipid biosynthetic pathways. In addition, we established a baseline for future lipidomic experiments in yeast. Finally, flexibility of lipidomic features is proposed as a new parameter for the description of the physiological state of an organism.

    doi.org/10.1371/journal.pone.0035063

    academia
    cells, yeast, method
  101. PLOS One, 2012

    101LipidXplorer: a software for consensual cross-platform lipidomics

    Ronny Herzog, Kai Schuhmann, Dominik Schwudke, Júlio L Sampaio, Stefan R Bornstein, Michael Schroeder, Andrej Shevchenko

    Abstract

    LipidXplorer is the open source software that supports the quantitative characterization of complex lipidomes by interpreting large datasets of shotgun mass spectra. LipidXplorer processes spectra acquired on any type of tandem mass spectrometers; it identifies and quantifies molecular species of any ionizable lipid class by considering any known or assumed molecular fragmentation pathway independently of any resource of reference mass spectra. It also supports any shotgun profiling routine, from high throughput top-down screening for molecular diagnostic and biomarker discovery to the targeted absolute quantification of low abundant lipid species.

    doi.org/10.1371/journal.pone.0029851

    academia
    software
  102. Structure, 2011

    102Cell membranes: the lipid perspective

    Ünal Coskun, Kai Simons

    Abstract

    Although cell membranes are packed with proteins mingling with lipids, remarkably little is known about how proteins interact with lipids to carry out their function. Novel analytical tools are revealing the astounding diversity of lipids in membranes. The issue is now to understand the cellular functions of this complexity. In this Perspective, we focus on the interface of integral transmembrane proteins and membrane lipids in eukaryotic cells. Clarifying how proteins and lipids interact with each other will be important for unraveling membrane protein structure and function. Progress toward this goal will be promoted by increasing overlap between different fields that have so far operated without much crosstalk.

    doi.org/10.1016/j.str.2011.10.010

    academia
    basic science
  103. Genome Biology, 2011

    103A novel informatics concept for high-throughput shotgun lipidomics based on the molecular fragmentation query language

    Ronny Herzog, Dominik Schwudke, Kai Schuhmann, Júlio L Sampaio, Stefan R Bornstein, Michael Schroeder, Andrej Shevchenko

    Abstract

    Shotgun lipidome profiling relies on direct mass spectrometric analysis of total lipid extracts from cells, tissues or organisms and is a powerful tool to elucidate the molecular composition of lipidomes. We present a novel informatics concept of the molecular fragmentation query language implemented within the LipidXplorer open source software kit that supports accurate quantification of individual species of any ionizable lipid class in shotgun spectra acquired on any mass spectrometry platform.

    doi.org/10.1186/gb-2011-12-1-r8

    academia
    software
  104. Nature reviews molecular cell biology, 2010

    104Revitalizing membrane rafts: new tools and insights

    Kai Simons, Mathias J Gerl

    Abstract

    Ten years ago, we wrote a Review on lipid rafts and signalling in the launch issue of Nature Reviews Molecular Cell Biology. At the time, this field was suffering from ambiguous methodology and imprecise nomenclature. Now, new techniques are deepening our insight into the dynamics of membrane organization. Here, we discuss how the field has matured and present an evolving model in which membranes are occupied by fluctuating nanoscale assemblies of sphingolipids, cholesterol and proteins that can be stabilized into platforms that are important in signalling, viral infection and membrane trafficking.

    doi.org/10.1038/nrm2977

    academia
    basic science
  105. Nature reviews molecular cell biology, 2010

    105Lipidomics: coming to grips with lipid diversity

    Andrej Shevchenko, Kai Simons

    Abstract

    Although lipids are biomolecules with seemingly simple chemical structures, the molecular composition of the cellular lipidome is complex and, currently, poorly understood. The exact mechanisms of how compositional complexity affects cell homeostasis and its regulation also remain unclear. This emerging field is developing sensitive mass spectrometry technologies for the quantitative characterization of the lipidome. Here, we argue that lipidomics will become an essential tool kit in cell and developmental biology, molecular medicine and nutrition.

    doi.org/10.1038/nrm2934

    academia
    clinical, diet, method
  106. nature reviews drug discovery, 2010

    106Subcellular targeting strategies for drug design and delivery

    Lawrence Rajendran, Hans-Joachim Knölker, Kai Simons

    Abstract

    Many drug targets are localized to particular subcellular compartments, yet current drug design strategies are focused on bioavailability and tissue targeting and rarely address drug delivery to specific intracellular compartments. Insights into how the cell traffics its constituents to these different cellular locations could improve drug design. In this Review, we explore the fundamentals of membrane trafficking and subcellular organization, as well as strategies used by pathogens to appropriate these mechanisms and the implications for drug design and delivery.

    doi.org/10.1038/nrd2897

    academia
    pharma
  107. Science, 2010

    107Lipid rafts as a membrane-organizing principle

    Daniel Lingwood, Kai Simons

    Abstract

    Cell membranes display a tremendous complexity of lipids and proteins designed to perform the functions cells require. To coordinate these functions, the membrane is able to laterally segregate its constituents. This capability is based on dynamic liquid-liquid immiscibility and underlies the raft concept of membrane subcompartmentalization. Lipid rafts are fluctuating nanoscale assemblies of sphingolipid, cholesterol, and proteins that can be stabilized to coalesce, forming platforms that function in membrane signaling and trafficking. Here we review the evidence for how this principle combines the potential for sphingolipid-cholesterol self-assembly with protein specificity to selectively focus membrane bioactivity.

    doi.org/10.1126/science.1174621

    academia
    basic science

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