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Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase dependent regulation of the orphan nuclear receptor SHP

¹Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea
²Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
³College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju, Korea
⁴Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreation to reactive Oxygen species, Kyung Hee University College of Medicine. Seoul, Republic of Korea
⁵Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea
⁶Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea

Objective: Metformin is an antidiabetic drug which is commonly used to treat type 2 diabetes. The aim of the study was to determine whether metformin regulates hepatic gluconeogenesis through the orphan nuclear receptor small heterodimer partner (SHP; NR0B2).

Research Design and Methods: We assessed the regulation of hepatic SHP gene expression by Northern blot analysis with metformin and adenovirus containing constitutive active form of AMPK (Ad-AMPK), and evaluated SHP, PEPCK, and G6Pase promoter activities via transient transfection assays in hepatocytes. Knockdown of SHP using siRNA SHP was conducted to characterize the metformin-induced inhibition of hepatic gluconeogenic gene expression in hepatocytes, and metformin- and Ad-SHP-mediated hepatic glucose production was measured in B6-Lep^ob/ob mice.

Results: Hepatic SHP gene expression was induced by metformin, AICAR, and Ad-AMPK. Metformin-induced SHP gene expression was abolished by adenovirus containing dominant negative form of AMPK (Ad-DN AMPK), as well as by compound C. Metformin inhibited HNF-4- or FoxA2-mediated promoter activity of PEPCK, G6Pase, and the inhibition was blocked with siRNA SHP. Additionally, SHP knockdown by adenovirus containing siRNA SHP (Ad-siRNA SHP) inhibited metformin-mediated repression of cAMP/dexamethasone-induced hepatic gluconeogenic gene expression. Furthermore, oral administration of metformin increased SHP mRNA levels in B6-Lep^ob/ob mice. Overexpression of SHP by Ad-SHP decreased blood glucose levels and hepatic gluconeogenic gene expression in B6-Lep^ob/ob mice.

Conclusion: We have concluded that metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase dependent regulation of SHP.

Key Words: Metformin • Orphan nuclear receptor • SHP • AMPK • G6Pase • PEPCK

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