Ceramides – Lipotoxic Inducers of Metabolic Disorders

In obesity and dyslipidemia, the oversupply of fat to tissues not suited for lipid storage induces cellular dysfunction that underlies diabetes and cardiovascular disease (i.e., lipotoxicity). Of the myriad lipids that accrue under these conditions, sphingolipids such as ceramide or its metabolites are amongst the most deleterious because they disrupt insulin sensitivity, pancreatic β cell function, vascular reactivity, and mitochondrial metabolism. Remarkably, inhibiting ceramide biosynthesis or catalyzing ceramide degradation in rodents ameliorates many metabolic disorders including diabetes, cardiomyopathy, insulin resistance, atherosclerosis, and steatohepatitis. Herein we discuss and critically assess studies that identify sphingolipids as major contributors to the tissue dysfunction underlying metabolic pathologies, highlighting the need to further decipher the full array of benefits elicited by ceramide depletion.

TrendsInhibition of ceramide biosynthesis ameliorates virtually all metabolic disorders in rodents.Lipidomic profiling studies have generally shown increased ceramides in relation to various disease endpoints, but discordance between studies has created controversy.Mechanisms of ceramide action include inhibition of insulin and growth factor signaling and action, impairment of mitochondrial lipid oxidation, ER stress, and induction of apoptosis.Adiponectin elicits its broad spectrum of metabolic actions by catalyzing ceramide deacylation via ceramidase activation.Inflammatory agents selectively upregulate the sphingolipid pathway, and this is essential for their induction of insulin resistance.