title: GPR119: a promising target for nonalcoholic fatty liver disease.
abstract: Nonalcoholic fatty liver disease is associated with metabolic syndrome and has the unique characteristic of excess lipid accumulation in liver. G-protein-coupled receptor 119 (GPR119) is a promising target for type 2 diabetes. However, the role of GPR119 activation in hepatic steatosis and its precise mechanism has not been investigated. In primary cultured hepatocytes from wild-type and GPR119 knockout (KO) mice, expression of lipogenic enzymes was elevated in GPR119 KO hepatocytes. Treatment of hepatocytes and HepG2 cells with GPR119 agonists in phase 2 clinical trials (MBX-2982 [MBX] and GSK1292263) inhibited protein expression of both nuclear and total sterol regulatory element binding protein (SREBP)-1, a key lipogenesis transcription factor. Oral administration of MBX in mice fed a high-fat diet potently inhibited hepatic lipid accumulation and expression levels of SREBP-1 and lipogenesis-related genes, whereas the hepatic antilipogenesis effects of MBX were abolished in GPR119 KO mice. MBX activated AMPK and increased Ser-372 phosphorylation of SREBP-1c, an inhibitory form of SREBP-1c. Moreover, inhibition of AMPK recovered MBX-induced down-regulation of SREBP-1. These findings demonstrate for the first time that the GPR119 ligand alleviates hepatic steatosis by inhibiting SREBP-1-mediated lipogenesis in hepatocytes.
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Han Yang University, Seoul, Republic of Korea; Department of Pathology, College of Medicine, Chosun University, Gwangju, Republic of Korea; College of Pharmacy, Dongguk University, Goyang, Republic of Korea; and College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Yang
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Han Yang University, Seoul, Republic of Korea; Department of Pathology, College of Medicine, Chosun University, Gwangju, Republic of Korea; College of Pharmacy, Dongguk University, Goyang, Republic of Korea; and College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Hyo Seon
authors.initials: HS
authors.lastname: Kim
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Han Yang University, Seoul, Republic of Korea; Department of Pathology, College of Medicine, Chosun University, Gwangju, Republic of Korea; College of Pharmacy, Dongguk University, Goyang, Republic of Korea; and College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Im
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Han Yang University, Seoul, Republic of Korea; Department of Pathology, College of Medicine, Chosun University, Gwangju, Republic of Korea; College of Pharmacy, Dongguk University, Goyang, Republic of Korea; and College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Kim
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Han Yang University, Seoul, Republic of Korea; Department of Pathology, College of Medicine, Chosun University, Gwangju, Republic of Korea; College of Pharmacy, Dongguk University, Goyang, Republic of Korea; and College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Dae Won
authors.initials: DW
authors.lastname: Jun
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Han Yang University, Seoul, Republic of Korea; Department of Pathology, College of Medicine, Chosun University, Gwangju, Republic of Korea; College of Pharmacy, Dongguk University, Goyang, Republic of Korea; and College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Sung Chul
authors.initials: SC
authors.lastname: Lim
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Han Yang University, Seoul, Republic of Korea; Department of Pathology, College of Medicine, Chosun University, Gwangju, Republic of Korea; College of Pharmacy, Dongguk University, Goyang, Republic of Korea; and College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Kyeong
authors.initials: K
authors.lastname: Lee
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Han Yang University, Seoul, Republic of Korea; Department of Pathology, College of Medicine, Chosun University, Gwangju, Republic of Korea; College of Pharmacy, Dongguk University, Goyang, Republic of Korea; and College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Jong Min
authors.initials: JM
authors.lastname: Choi
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Han Yang University, Seoul, Republic of Korea; Department of Pathology, College of Medicine, Chosun University, Gwangju, Republic of Korea; College of Pharmacy, Dongguk University, Goyang, Republic of Korea; and College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Sang Kyum
authors.initials: SK
authors.lastname: Kim
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea; Department of Internal Medicine, Han Yang University, Seoul, Republic of Korea; Department of Pathology, College of Medicine, Chosun University, Gwangju, Republic of Korea; College of Pharmacy, Dongguk University, Goyang, Republic of Korea; and College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea kwkang@snu.ac.kr.
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008698:Mesylates / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C587902:(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methyl methanesulfonate; C516207:Gpr119 protein, mouse; C000608114:MBX-2982; D008698:Mesylates; D010069:Oxadiazoles; D043562:Receptors, G-Protein-Coupled; D051780:Sterol Regulatory Element Binding Protein 1; D013777:Tetrazoles; D013844:Thiazoles; D055372:AMP-Activated Protein Kinases
keywords: AMPK; SREBP-1; steatosis