Sphingolipids, Insulin Resistance, and Metabolic Disease: New Insights from in Vivo Manipulation of Sphingolipid Metabolism
Obesity and dyslipidemia are risk factors for metabolic disorders including diabetes and cardiovascular disease. Sphingolipids such as ceramide and glucosylceramides, while being a relatively minor component of the lipid milieu in most tissues, may be among the most pathogenic lipids in the onset of the sequelae associated with excess adiposity. Circulating factors associated with obesity (e.g., saturated fatty acids, inflammatory cytokines) selectively induce enzymes that promote sphingolipid synthesis, and lipidomic profiling reveals relationships between tissue sphingolipid levels and certain metabolic diseases. Moreover, studies in cultured cells and isolated tissues implicate sphingolipids in certain cellular events associated with diabetes and cardiovascular disease, including insulin resistance, pancreatic -cell failure, cardiomyopathy, and vascular dysfunction. However, definitive evidence that sphingolipids contribute to insulin resistance, diabetes, and atherosclerosis has come only recently, as researchers have found that pharmacological inhibition or genetic ablation of enzymes controlling sphingolipid synthesis in rodents ameliorates each of these conditions. Herein we will review the role of ceramide and other sphingolipid metabolites in insulin resistance, -cell failure, cardiomyopathy, and vascular dysfunction, focusing on these in vivo studies that identify enzymes controlling sphingolipid metabolism as therapeutic targets for combating metabolic disease. (Endocrine Reviews 29: 381-402, 2008) I. Introduction II. Regulation of Sphingolipid Synthesis and Metabolism: Effect of Obesity A. Sphingolipids in the diet B. Regulation of sphingolipid synthesis and metabolism during obesity C. Quantification of sphingolipid levels during obesity III. Sphingolipids in Atherosclerosis A. Modulation of sphingolipid levels prevents plaque formation in ApoE-deficient mice B. Mechanism by which sphingolipids promote atherosclerosis and thrombosis IV. Sphingolipids in Insulin Resistance A. Modulating sphingolipid levels impacts insulin sensitivity in vivo B. Mechanism by which sphingolipids antagonize insulin action V. Sphingolipids in Pancreatic -Cell Failure A. Modulating sphingolipid levels impacts the -cell in rodent models of diabetes B. Mechanism of ceramide-mediated -cell failure C. Mechanism of glucoslyceramide-mediated -cell failure D. S1P as a regulator of -cell growth and survival VI. Sphingolipids in Cardiomyopathy A. Modulating sphingolipid levels ameliorates cardiac dysfunction in a rodent model of lipotoxic cardiomyopathy B. Mechanism by which ceramides promote cardiomyocyte dysfunction and apoptosis VII. Conclusions and Considerations