Read the article about Multi-OMICS for Risk Assessment and Progression of Diabetes within the IMI2 project RHAPSODY by Kirsten Leufgen (SCIPROM) and Oliver Uecke (Lipotype GmbH) in the German Magazine Transkript/Laborwelt (04/2017)
The month of August came with a set of newly-published lipidomics publications which made use of Lipotype Shotgun Lipidomics.
Chronic kidney disease Clinical risk factors explain only a fraction of the variability of eGFR decline in people with type 2 diabetes. However, cross-omics technologies have the potential to identify additional biomarkers for the refinement of prognosis.
Putting together proteomics, metabolomics and lipidomics panel assay measurements and the clinical factor eGFR, the investigation unraveled the predictor biomarker KIM-1.
This is the first publication of the BEAt-DKD consortium which receives funding under IMI of the EU.
Nano-scale lipid organization The plasma membrane is composed of a complex lipid mixture that forms heterogeneous membrane environments. Physiological events are controlled by small-scale lipid organization.
The investigation unraveled that some proteins are critical for the synthesis of the lipid phosphatidylinositol (4,5)-bisphosphate, a key regulator of dynamic events at the plasma membrane. Ultimately, they control global plasma membrane organization and dynamics.
Lipid droplet size Lipid droplet breakdown in hepatocytes (liver cells) is mediated by a combination of lipolysis and a selective autophagic mechanism called lipophagy. However, the relationship of these seemingly distinct pathways remained unclear – until now.
This study found that inhibition of lipolysis, lipophagy, or both resulted in similar overall lipid droplet content but dramatic differences in their form. Inhibition of the lipolysis enzyme ATGL resulted in large cytoplasmic lipid droplets, whereas lysosomal inhibition caused the accumulation of numerous small ones within the cytoplasm. The combination of both resulted in large droplets.
Alterations of the liver in diabetes The liver regulates the availability of insulin to other tissues. It is the first organ physiologically exposed to higher insulin concentrations. The molecular consequences of chronic insulin deficiency for the liver have now been studied systematically.
The analyses revealed increased activities in amino acid metabolism, oxidation of fatty acids, ketogenesis, and gluconeogenesis in the liver 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.
Understanding the genetics of lipid species offers information beyond that provided by routine lipid screening, and can help improve risk prediction and treatment. In the first large-scale study, novel lipid-associated genetic variants were identified, some of which were linked with risk for cardiovascular disease, such as heart attacks and strokes. Lipotype provided the technology to measure these lipids – Lipotype Shotgun Lipidomics.
The human blood plasma lipidome Human plasma comprises hundreds of lipid species which differ in chemical structure and function. Many of these are known risk factors for human diseases. Advances in mass spectrometry-driven lipid analysis – lipidomics – has made it possible to study the patient lipidome to a greater extent than is possible with conventional analytical methods. Currently, however, understanding the genetic regulation of molecular lipid species is lacking. Unraveling this information could help in the personalized management of atherosclerosis and heart disease.
In light of this, this collaborative project involving centres in Finland, Germany and the USA integrated information from the lipidome, genome and phenome to answer key questions relating to the heritability of lipid species, including: Which genetic variants influence plasma levels of lipid species? How do these variants relate to disease outcomes and what is the underlying mechanisms?
The answers are… 1. Lipid species are heritable. Lipid species heritability ranges from 10 to 54 per cent, with the highest heritability in lipids containing polyunsaturated fatty acids (PUFAs). These findings are important given renewed interest in the role of PUFAs in cardiovascular disease.
2. GWAS analyses identified 35 gene variants associated with lipids. Using clinical outcome data, the investigators showed that 10 of these variants were associated with cardiovascular disease. In addition, 3 gene variants at the were associated with type 2 diabetes. This information could help drive the development of new treatment targets.
3. Further notes on lipid metabolism. The study also provided clues to the underlying mechanisms of well-known lipid loci on lipid metabolism and cardiovascular disease risk.
Lipotype put online a new biotech & dermatology customer reference with Aldeyra Therapeutics about lipid analysis for topical dermal drug development for the treatment of ichthyosis associated with SLS.
The project in short Sjögren-Larsson Syndrome (SLS) is a rare inborn error of aldehyde metabolism characterized by severe skin thickening (ichthyosis), retinal disease, and neurological dysfunction. As of today, no therapy that addresses SLS has been approved. Aldeyra Therapeutics has conducted a Phase 2 randomized, parallel-group, double-blind, vehicle-controlled, multi-center clinical trial of topical dermal reproxalap for the treatment of ichthyosis associated with SLS. The results of the trial demonstrated clinically meaningful and statistically significant improvements of SLS skin symptoms of patients after only eight weeks of treatment. A multi-center Phase 3 clinical trial is ongoing.
What Lipotype did Lipotype Shotgun Skin Lipidomics provided Aldeyra Therapeutics with lipid analysis of skin samples for identification of relevant lipid biomarkers in the Phase 2 clinical trial. Results of the skin lipidomics analysis delivered evidence for a correlation between clinical effects and those skin lipid biomarkers. Consistent with the clinical activity of reproxalap, significant dermal biomarker changes were noted in reproxalap-treated patients but not vehicle-treated patients. Cholesterol, which is significantly elevated in the skin of SLS patients, was reduced in reproxalap-treated patients more than in vehicle-treated patients.
About Aldeyra Therapeutics Aldeyra Therapeutics is a biotechnology company devoted to improving lives by inventing, developing, and commercializing next-generation medicines that treat immune-mediated and metabolic diseases. Aldeyra’s lead product candidate, reproxalap (formerly called NS2), is a small molecule RASP (Reactive Aldehyde Species) inhibitor in Phase 3 clinical development for the treatment of dry eye disease, allergic conjunctivitis, noninfectious anterior uveitis, and Sjögren-Larsson syndrome. With its focus on a carefully selected range of diseases, Aldeyra Therapeutics is devoted to improving lives through outstanding innovation.
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