title: CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance.
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.
authors.affiliation: Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Suryaprakash
authors.initials: S
authors.lastname: Raichur
authors.affiliation: Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Siew Tein
authors.initials: ST
authors.lastname: Wang
authors.affiliation: Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Puck Wee
authors.initials: PW
authors.lastname: Chan
authors.affiliation: Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Ching
authors.forename: Bhagirath
authors.initials: B
authors.lastname: Chaurasia
authors.affiliation: Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Bghagirath
authors.initials: B
authors.lastname: Chaurasia
authors.affiliation: Singapore Institute for Clinical Sciences, Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore 117609, Singapore.
authors.forename: Shaillay
authors.initials: S
authors.lastname: Dogra
authors.affiliation: Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Miina K
authors.initials: MK
authors.lastname: Öhman
authors.affiliation: Singapore Bioimaging Consortium, 02-02 Helios, Biopolis, Singapore 138667, Singapore.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Takeda
authors.affiliation: 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.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sugii
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Pewzner-Jung
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
authors.affiliation: 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.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Summers
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism; D015243:Cholesterol, VLDL / Q000097:blood; D059305:Diet, High-Fat; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology / Q000627:therapeutic use; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D057809:HEK293 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007333:Insulin Resistance; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051049:Sphingosine N-Acyltransferase / Q000235:genetics / Q000378:metabolism*
chemical_list: D002518:Ceramides; D015243:Cholesterol, VLDL; D045222:Electron Transport Chain Complex Proteins; D005229:Fatty Acids, Monounsaturated; D047495:PPAR gamma; D011506:Proteins; D012333:RNA, Messenger; C525805:fat-specific protein 27, mouse; C580723:Cers2 protein, mouse; D051049:Sphingosine N-Acyltransferase; C001996:thermozymocidin