CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance.

Published

Journal Article

Inhibition of ceramide synthesis prevents diabetes, steatosis, and cardiovascular disease in rodents. Six different ceramide synthases (CerS) that differ in tissue distribution and substrate specificity account for the diversity in acyl-chain composition of distinct ceramide species. Haploinsufficiency for ceramide synthase 2 (CerS2), the dominant isoform in the liver that preferentially makes very-long-chain (C22/C24/C24:1) ceramides, led to compensatory increases in long-chain C16-ceramides and conferred susceptibility to diet-induced steatohepatitis and insulin resistance. Mechanistic studies revealed that these metabolic effects were likely due to impaired β-oxidation resulting from inactivation of electron transport chain components. Inhibiting global ceramide synthesis negated the effects of CerS2 haploinsufficiency in vivo, and increasing C16-ceramides by overexpressing CerS6 recapitulated the phenotype in isolated, primary hepatocytes. Collectively, these studies reveal that altering sphingolipid acylation patterns impacts hepatic steatosis and insulin sensitivity and identify CerS6 as a possible therapeutic target for treating metabolic diseases associated with obesity.

Full Text

Cited Authors

  • Raichur, S; Wang, ST; Chan, PW; Li, Y; Ching, J; Chaurasia, B; Dogra, S; Öhman, MK; Takeda, K; Sugii, S; Pewzner-Jung, Y; Futerman, AH; Summers, SA

Published Date

  • October 2014

Published In

Volume / Issue

  • 20 / 4

Start / End Page

  • 687 - 695

PubMed ID

  • 25295789

Pubmed Central ID

  • 25295789

Electronic International Standard Serial Number (EISSN)

  • 1932-7420

International Standard Serial Number (ISSN)

  • 1550-4131

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2014.09.015

Language

  • eng