Sphingolipids, Insulin Resistance, and Metabolic Disease: New Insights from in Vivo Manipulation of Sphingolipid Metabolism
William L. Holland and
Scott A. Summers
Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84132
Correspondence: Address all correspondence and requests for reprints to: Scott A. Summers, Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84132. E-mail: Scott.Summers{at}hsc.utah.edu
Obesity and dyslipidemia are risk factors for metabolic disordersincluding diabetes and cardiovascular disease. Sphingolipidssuch as ceramide and glucosylceramides, while being a relativelyminor component of the lipid milieu in most tissues, may beamong the most pathogenic lipids in the onset of the sequelaeassociated with excess adiposity. Circulating factors associatedwith obesity (e.g., saturated fatty acids, inflammatory cytokines)selectively induce enzymes that promote sphingolipid synthesis,and lipidomic profiling reveals relationships between tissuesphingolipid levels and certain metabolic diseases. Moreover,studies in cultured cells and isolated tissues implicate sphingolipidsin certain cellular events associated with diabetes and cardiovasculardisease, including insulin resistance, pancreatic β-cellfailure, cardiomyopathy, and vascular dysfunction. However,definitive evidence that sphingolipids contribute to insulinresistance, diabetes, and atherosclerosis has come only recently,as researchers have found that pharmacological inhibition orgenetic ablation of enzymes controlling sphingolipid synthesisin rodents ameliorates each of these conditions. Herein we willreview the role of ceramide and other sphingolipid metabolitesin insulin resistance, β-cell failure, cardiomyopathy,and vascular dysfunction, focusing on these in vivo studiesthat identify enzymes controlling sphingolipid metabolism astherapeutic targets for combating metabolic disease.
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