1. Academic Validation
  2. GPR119: a promising target for nonalcoholic fatty liver disease

GPR119: a promising target for nonalcoholic fatty liver disease

  • FASEB J. 2016 Jan;30(1):324-35. doi: 10.1096/fj.15-273771.
Jin Won Yang 1 Hyo Seon Kim 1 Ji Hye Im 1 Ji Won Kim 1 Dae Won Jun 1 Sung Chul Lim 1 Kyeong Lee 1 Jong Min Choi 1 Sang Kyum Kim 1 Keon Wook Kang 2
Affiliations

Affiliations

  • 1 *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.
  • 2 *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 [email protected].
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.

Keywords

AMPK; SREBP-1; steatosis.

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