Sphingolipids, insulin resistance, and metabolic disease

New insights from in vivo manipulation of sphingolipid metabolism

William L. Holland, Scott A. Summers

Research output: Contribution to journalArticle

326 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)381-402
Number of pages22
JournalEndocrine Reviews
Volume29
Issue number4
DOIs
StatePublished - Jun 2008

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Sphingolipids
Metabolic Diseases
Insulin Resistance
Ceramides
Cardiomyopathies
Blood Vessels
Cardiovascular Diseases
Enzymes
Obesity
Glucosylceramides
Lipids
Adiposity
Dyslipidemias
Cultured Cells
Rodentia
Atherosclerosis
Fatty Acids
Research Personnel
Pharmacology
Cytokines

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Sphingolipids, insulin resistance, and metabolic disease : New insights from in vivo manipulation of sphingolipid metabolism. / Holland, William L.; Summers, Scott A.

In: Endocrine Reviews, Vol. 29, No. 4, 06.2008, p. 381-402.

Research output: Contribution to journalArticle

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