title: Suppression of PPARγ-mediated monoacylglycerol O-acyltransferase 1 expression ameliorates alcoholic hepatic steatosis.
abstract: Alcohol consumption is one of the major causes of hepatic steatosis, fibrosis, cirrhosis, and superimposed hepatocellular carcinoma. Ethanol metabolism alters the NAD(+)/NADH ratio, thereby suppressing the activity of sirtuin family proteins, which may affect lipid metabolism in liver cells. However, it is not clear how long-term ingestion of ethanol eventually causes lipid accumulation in liver. Here, we demonstrate that chronic ethanol ingestion activates peroxisome proliferator-activated receptor γ (PPARγ) and its target gene, monoacylglycerol O-acyltransferase 1 (MGAT1). During ethanol metabolism, a low NAD(+)/NADH ratio repressed NAD-dependent deacetylase sirtuin 1 (SIRT1) activity, concomitantly resulting in increased acetylated PPARγ with high transcriptional activity. Accordingly, SIRT1 transgenic mice exhibited a low level of acetylated PPARγ and were protected from hepatic steatosis driven by alcohol or PPARγ2 overexpression, suggesting that ethanol metabolism causes lipid accumulation through activation of PPARγ through acetylation. Among the genes induced by PPARγ upon alcohol consumption, MGAT1 has been shown to be involved in triglyceride synthesis. Thus, we tested the effect of MGAT1 knockdown in mice following ethanol consumption, and found a significant reduction in alcohol-induced hepatic lipid accumulation. These results suggest that MGAT1 may afford a promising approach to the treatment of fatty liver disease.
authors.affiliation: Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Institute of Genetic Science, Yonsei University College of Medicine, Seoul 120-752, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 120-752, Korea.
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Institute of Genetic Science, Yonsei University College of Medicine, Seoul 120-752, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 120-752, Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Song
authors.affiliation: Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Institute of Genetic Science, Yonsei University College of Medicine, Seoul 120-752, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 120-752, Korea.
authors.forename: Ara
authors.initials: A
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Institute of Genetic Science, Yonsei University College of Medicine, Seoul 120-752, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 120-752, Korea.
authors.forename: Yoonjeong
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Institute of Genetic Science, Yonsei University College of Medicine, Seoul 120-752, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 120-752, Korea.
authors.forename: Jo Woon
authors.initials: JW
authors.lastname: Seok
authors.affiliation: Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Institute of Genetic Science, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Division of Metabolic Disease, Center for Biomedical Sciences, National Institutes of Health, Cheongwon-gun, Chungbuk 363-951, Korea.
authors.forename: Yoo Jeong
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Kwan Sik
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Institute of Genetic Science, Yonsei University College of Medicine, Seoul 120-752, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 120-752, Korea.|Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Jae-Woo
authors.initials: JW
authors.lastname: Kim
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000431:Ethanol / Q000378:metabolism; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009243:NAD / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D047495:PPAR gamma; D009243:NAD; D000431:Ethanol; D000217:Acyltransferases; C021802:2-acylglycerol O-acyltransferase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1