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Metformin Inhibits Hepatic Gluconeogenesis Through AMP-Activated Protein Kinase–Dependent Regulation of the Orphan Nuclear Receptor SHP

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

Address correspondence and reprint requests to Hueng-Sik Choi, PhD, Hormone Research Center, School of Biological Sciences & Technology, Chonnam National University, Gwangju, 500-757, Republic of Korea. E-mail: hsc{at}chonnam.ac.kr

Abbreviations: ACC, acetyl-CoA carboxylase; Ad-AMPK, adenovirus AMPK; Ad-DN-AMPK, adenovirus dominant negative form of AMPK; Ad-SHP, adenovirus SHP; AICAR, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside; AMPK, AMP-activated protein kinase; CA-AMPK, constitutively active AMPK; DMEM, Dulbecco's modified Eagle's medium; DN-AMPK, dominant negative mutant AMPK; GAPDH, glyceraldehyde-3-phosphate-dehydrogenase; HNF, hepatocyte nuclear factor; LRH-1, liver receptor homolog-1; SF-1, steroidogenic factor-1; SHP, small heterodimer partner

OBJECTIVE—Metformin is an antidiabetic drug 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 a constitutive active form of AMP-activated protein kinase (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 adenovirus SHP (Ad-SHP)–mediated hepatic glucose production was measured in B6-Lep^ob/ob mice.

RESULTS—Hepatic SHP gene expression was induced by metformin, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), and Ad-AMPK. Metformin-induced SHP gene expression was abolished by adenovirus containing the dominant negative form of AMPK (Ad-DN-AMPK), as well as by compound C. Metformin inhibited hepatocyte nuclear factor-4–or FoxA2-mediated promoter activity of PEPCK and G6Pase, and the inhibition was blocked with siRNA SHP. Additionally, SHP knockdown by adenovirus containing 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.

CONCLUSIONS—We have concluded that metformin inhibits hepatic gluconeogenesis through AMPK-dependent regulation of SHP.

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