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Lipid droplets as dynamic organelles of fat deposition and release: Translational research towards human disease

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Metabolic diseases and lipid storage

Metabolic overload is a serious problem in developed countries as it is associated with secondary problems, including obesity, type-2 diabetes and atherosclerosis. A European consortium worked to find associations with alterations in the lipid profile and also unravel the complex network of lipids, genes and proteins.

Health

Lipids are cellular macromolecules, integral constituents of membranes, and central to the regulation of various cellular processes. Neutral lipids are stored in the form of lipid droplets (LDs), organelles that have recently emerged as the dynamic link between lipid and energy metabolism. The EU-funded LIPIDOMICNET study exploited recent developments in lipidomics to elucidate LD biogenesis and composition to define novel therapeutic targets and biomarkers. Using mass spectrometry, partners developed high-throughput methods along with bioinformatics tools for determining the lipid profile in lipid-related disorders after analysing various lipid species. To comprehend LD processing in liver and adipose, partners studied lipid–protein interactions and investigated the dynamics of fat deposition and release. Cell lines, patient samples and animal models including mice were used for testing. Study results provided mechanistic information related to the aberrant regulation of lipid storage and release. LD formation was specifically perturbed in the hepatocytes of animals suffering from metabolic disorders. The consortium identified several new pathways that are involved in both liver and adipocyte lipid processing. The lipid stress-response and its impact were studied in atherosclerotic lesions and especially in macrophages and neutrophils. Improvements in electron microscopy imaging enabled researchers to visualise lipid structures like lipoproteins and LDs. The entry of lipids into cells was also investigated in human diseases associated with endolysosomal lipid storage (phospholipidosis). The generated data has been organised as a detailed special purpose Wiki base . The processing of LDs was also examined in diabetic patients’ samples and key genes such as ATP10D were shown to be involved in disease onset. The consortium went on to combine their findings with lipidomic biomarkers identified during the EUROSPAN genome-wide association study (GWAS). This led to the identification of polymorphic genes in sphingolipid/fatty acid metabolism, which are significantly associated with circulating lipid species and diabetes development. Collectively, the information generated during the LIPIDOMICNET project provides a mechanistic picture of the role of LDs in metabolic disorders. Furthermore, the identified pathways and genes hold great clinical significance and could be used in future therapeutic interventions.

Keywords

LIPIDOMICNET

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