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Lipotoxicity is a key event in diabesity and vascular diseases associated with cytotoxicity, inflammation and apoptosis/proliferation.Plasma lipid species reflect cell/organelle dysfunctions and respond to gene polymorphisms related to sterol, sphingolipid, fatty acid (FA) and glycerophospholipid metabolism.The pro-inflammatory and cytotoxic oxysterols regulate cholesterol homeostasis via LXR, SREBP and HMG-CoA-reductase, and contribute to atherogenesis, DNA/chromatin damage and neurodegeneration.Ceramides are mediators of apoptosis, derived either from serine and palmitoyl-CoA, or from sphingosine-1-phosphate via the salvage pathway.FA-chain length, saturation and absolute ceramide levels affect protein trafficking, ER stress and apoptosis as targets of lipotoxicity.Plasmalogens preferentially transport prostanoid precursors [arachidonic (20:4n-6), docosapentaenoic (22:5n-6) and docosahexaenoic (22:6n-3) acids] released by phospholipase A2 (PLA2), to produce inflammatory mediators and lysoplasmalogens, enhancing membrane permeability.Free FAs (FFAs), elevated in diabesity, are easily oxidized or esterified into acylglycerols, and incorporated into lipoproteins and phospholipids.Lyso-phosphatidylcholine (LPC) is generated together with FFAs from phosphatidylcholine (PC) by LCAT and PLA2.Enhanced tissue concentrations of LPC occur in diabesity, being a principal mediator of FFA-related cytotoxicity and lipoapoptosis.Since not all LPCs and ceramides are proinflammatory and lipotoxic, single lipid species were analyzed to identify biomarkers in epidemiological and cohort studies with genetic and lifestyle risk for diabesity and vascular morbidity and mortality.SNPs ofATP10D gene and FADS cluster associate with sphingolipid and glycerophospholipid species and vascular-and metabolic disease.The mortality association of sphingolipid species depends on chain length and saturation.Saturated and monounsaturated PCs positively correlate with mortality, while highly polyunsaturated (n-3) PCs indicate survival.Almost all PCs and LPCs are significantly increased in hypertension with insulin resistance (IR) compared to IR-individuals without hypertension.LPCs are decreased in obese IR-individuals as compared to IR-patients without abdominal obesity.A mild decrease of PCs is also observed, except of PCs with 3-4 times unsaturated FA-chains that are slightly elevated.In atherogenic dyslipidaemia LPCs and ceramides are also elevated.Taken together, proper desaturation and elongation of FAs that are later incorporated in glycerophospholipids, sphingolipids and glycosphingolipids, or stored in lipid droplets, are critical for abnormalities in the lipidome ultimately leading to vascular-and metabolic disease.