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Cell Metab. 2014 Oct 7;20(4):687-95. doi: 10.1016/j.cmet.2014.09.015.

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

Author information

1
Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
2
Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore 117609, Singapore.
3
Singapore Bioimaging Consortium, 02-02 Helios, Biopolis, Singapore 138667, Singapore.
4
Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore 169857, Singapore; Singapore Bioimaging Consortium, 02-02 Helios, Biopolis, Singapore 138667, Singapore.
5
Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
6
Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore 169857, Singapore; Singapore Bioimaging Consortium, 02-02 Helios, Biopolis, Singapore 138667, Singapore. Electronic address: scott.summers@duke-nus.edu.sg.

Erratum in

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 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.

Comment in

PMID:
25295789
DOI:
10.1016/j.cmet.2014.09.015
[Indexed for MEDLINE]
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