Sphingolipids, Insulin Resistance, and Metabolic Disease: New Insights from in Vivo Manipulation of Sphingolipid Metabolism

WL Holland, SA Summers - Endocrine reviews, 2008 - academic.oup.com
WL Holland, SA Summers
Endocrine reviews, 2008academic.oup.com
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 (eg., saturated fatty acids, inflammatory cytokines)
selectively induce enzymes that promote sphingolipid synthesis, and lipidomic profiling …
Abstract
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 β-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, β-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.
Oxford University Press