Journal article
CerS2 Haploinsufficiency Inhibits beta-Oxidation and Confers Susceptibility to Diet-Induced Steatohepatitis and Insulin Resistance
Cell Metabolism, Vol.20(4), pp.687-695
Oct/2014
Abstract
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 beta-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.
Details
- Title
- CerS2 Haploinsufficiency Inhibits beta-Oxidation and Confers Susceptibility to Diet-Induced Steatohepatitis and Insulin Resistance
- Creators
- Suryaprakash Raichur (null)Siew Tein Wang (null)Puck Wee Chan (null)Ying Li (null)Jianhong Ching (null)Bhagirath Chaurasia (null)Shaillay Dogra (null)Miina K. Oehman (null)Kosuke Takeda (null)Shigeki Sugii (null)Yael Pewzner-Jung (null) - 972WIS_INST___112Anthony H. Futerman (null) - 972WIS_INST___112Scott A. Summers (null)
- Resource Type
- Journal article
- Publication Details
- Cell Metabolism, Vol.20(4), pp.687-695; Oct/2014
- Number of pages
- 9
- Language
- English
- DOI
- https://doi.org/10.1016/j.cmet.2014.09.015
- Grant note
- National Medical Research Council [CBG/0053/2013]; Singapore Ministry of Education Academic Research Fund [MOE2009-T2-2-016]; Duke-NUS Signature Research Program - Ministry of Health, SingaporeThis work was supported by the National Medical Research Council (CBG/0053/2013 to S. A. S.), the Singapore Ministry of Education Academic Research Fund (MOE2009-T2-2-016 to S. A. S.), and the Duke-NUS Signature Research Program funded by the Ministry of Health, Singapore (to S. A. S.). The metabolomics profiling was done by the Duke-NUS Metabolomics Facility. A. H. F. is the Joseph Meyerhoff Professor of Biochemistry at the Weizmann Institute of Science._ALMAME_DELIMITER_
- Record Identifier
- 993265664803596
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