title: Nuclear receptor PPARγ-regulated monoacylglycerol O-acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet-induced hepatic steatosis.
abstract: Recently, hepatic peroxisome proliferator-activated receptor (PPAR)γ has been implicated in hepatic lipid accumulation. We found that the C3H mouse strain does not express PPARγ in the liver and, when subject to a high-fat diet, is resistant to hepatic steatosis, compared with C57BL/6 (B6) mice. Adenoviral PPARγ2 injection into B6 and C3H mice caused hepatic steatosis, and microarray analysis demonstrated that hepatic PPARγ2 expression is associated with genes involved in fatty acid transport and the triglyceride synthesis pathway. In particular, hepatic PPARγ2 expression significantly increased the expression of monoacylglycerol O-acyltransferase 1 (MGAT1). Promoter analysis by luciferase assay and electrophoretic mobility shift assay as well as chromatin immunoprecipitation assay revealed that PPARγ2 directly regulates the MGAT1 promoter activity. The MGAT1 overexpression in cultured hepatocytes enhanced triglyceride synthesis without an increase of PPARγ expression. Importantly, knockdown of MGAT1 in the liver significantly reduced hepatic steatosis in 12-wk-old high-fat-fed mice as well as ob/ob mice, accompanied by weight loss and improved glucose tolerance. These results suggest that the MGAT1 pathway induced by hepatic PPARγ is critically important in the development of hepatic steatosis during diet-induced obesity.
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, Korea.
authors.forename: Yoo Jeong
authors.initials: YJ
authors.lastname: Lee
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Ko
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Eunha
authors.initials: E
authors.lastname: Kim
authors.forename: Hyemin
authors.initials: H
authors.lastname: Lee
authors.forename: Hyeonjin
authors.initials: H
authors.lastname: Choi
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Yu
authors.forename: Hyo Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Je-Kyung
authors.initials: JK
authors.lastname: Seong
authors.forename: Kyung-Sup
authors.initials: KS
authors.lastname: Kim
authors.forename: Jae-woo
authors.initials: JW
authors.lastname: Kim
mesh_terms: D000217:Acyltransferases / Q000096:biosynthesis*; D000256:Adenoviridae / Q000235:genetics; D000821:Animal Feed; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D008055:Lipids / Q000737:chemistry*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D017351:N-Acetylglucosaminyltransferases; D047495:PPAR gamma / Q000096:biosynthesis / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D008055:Lipids; D047495:PPAR gamma; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000217:Acyltransferases; C459903:MGAT1 protein, mouse; D017351:N-Acetylglucosaminyltransferases