CerS2 Haploinsufficiency Inhibits β-Oxidation and Confers Susceptibility to Diet-Induced Steatohepatitis and Insulin Resistance
2014; Cell Press; Volume: 20; Issue: 4 Linguagem: Inglês
10.1016/j.cmet.2014.09.015
ISSN1932-7420
AutoresSuryaprakash Raichur, Siew Tein Wang, Puck Wee Chan, Ying Li, Jianhong Ching, Bhagirath Chaurasia, Shaillay Kumar Dogra, Miina K. Öhman, Kosuke Takeda, Shigeki Sugii, Yael Pewzner‐Jung, Anthony H. Futerman, Scott A. Summers,
Tópico(s)Lipid metabolism and biosynthesis
ResumoInhibition 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.
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