title: Monoacylglycerol O-acyltransferase 1 is regulated by peroxisome proliferator-activated receptor γ in human hepatocytes and increases lipid accumulation.
abstract: Monoacylglycerol O-acyltransferase (MGAT) is an enzyme that is involved in triglyceride synthesis by catalyzing the formation of diacylglycerol from monoacylglycerol and fatty acyl CoAs. Recently, we reported that MGAT1 has a critical role in hepatic TG accumulation and that its suppression ameliorates hepatic steatosis in a mouse model. However, the function of MGAT enzymes in hepatic lipid accumulation has not been investigated in humans. Unlike in rodents, MGAT3 as well as MGAT1 and MGAT2 are present in humans. In this study, we evaluated the differences between MGAT subtypes and their association with peroxisome proliferator-activated receptor γ (PPARγ), a regulator of mouse MGAT1 expression. In human primary hepatocytes, basal expression of MGAT1 was lower than that of MGAT2 or MGAT3, but was strongly induced by PPARγ overexpression. A luciferase assay as well as an electromobility shift assay revealed that human MGAT1 promoter activity is driven by PPARγ by direct binding to at least two regions of the promoter in 293T and HepG2 cells. Moreover, siRNA-mediated suppression of MGAT1 expression significantly attenuated lipid accumulation by PPARγ overexpression in HepG2 cells, as evidenced by oil-red-O staining. These results suggest that human MGAT1 has an important role in fatty liver formation as a target gene of PPARγ, and blocking MGAT1 activity could be an efficient therapeutic way to reduce nonalcoholic fatty liver diseases in humans.
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, Republic of Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 120-752, Republic of Korea.
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Yu
authors.affiliation: Division of Metabolic Disease, Center for Biomedical Sciences, National Institutes of Health, Cheongwon-gun, Chungbuk 363-951, Republic of Korea.
authors.forename: Yoo Jeong
authors.initials: YJ
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, Republic of Korea.
authors.forename: Hyo Jung
authors.initials: HJ
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, Republic of Korea.
authors.forename: Hyeonjin
authors.initials: H
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, Republic of Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 120-752, Republic of 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, Republic of Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 120-752, Republic of 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, Republic of Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 120-752, Republic of Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea. Electronic address: japol13@yuhs.ac.
authors.forename: Jae-woo
authors.initials: JW
authors.lastname: Kim
mesh_terms: D000217:Acyltransferases / Q000378:metabolism*; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D022781:Hepatocytes / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D047495:PPAR gamma / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D047495:PPAR gamma; D000217:Acyltransferases; C021802:2-acylglycerol O-acyltransferase
keywords: Hepatic steatosis; MGAT1; PPARγ; Primary hepatocytes; Promoter