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
10/07/2014
DOI: 10.1016/j.cmet.2014.09.015
PMID: 25295789
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: Subtitle
- CerS2 Haploinsufficiency Inhibits beta-Oxidation and Confers Susceptibility to Diet-Induced Steatohepatitis and Insulin Resistance
- Creators
- Suryaprakash Raichur - National University of SingaporeSiew Tein Wang - National University of SingaporePuck Wee Chan - National University of SingaporeYing Li - National University of SingaporeJianhong Ching - National University of SingaporeBhagirath Chaurasia - National University of SingaporeShaillay Dogra - Singapore Institute for Clinical SciencesMiina K. Oehman - National University of SingaporeKosuke Takeda - Singapore Bioimaging ConsortiumShigeki Sugii - National University of SingaporeYael Pewzner-Jung - Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, IsraelAnthony H. Futerman - Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, IsraelScott A. Summers - National University of Singapore
- Resource Type
- Journal article
- Publication Details
- Cell metabolism, Vol.20(4), pp.687-695
- Publisher
- Elsevier
- DOI
- 10.1016/j.cmet.2014.09.015
- PMID
- 25295789
- ISSN
- 1550-4131
- eISSN
- 1932-7420
- Number of pages
- 9
- Grant note
- MOE2009-T2-2-016 / Singapore Ministry of Education Academic Research Fund; Ministry of Education, Singapore Duke-NUS Signature Research Program - Ministry of Health, Singapore; Ministry of Health-Singapore; National University of Singapore CBG/0053/2013 / National Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC)
- Language
- English
- Date published
- 10/07/2014
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359882602771
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