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- Title
Metformin Inhibits Growth Hormone--Mediated Hepatic PDK4 Gene Expression Through Induction of Orphan Nuclear Receptor Small Heterodimer Partner.
- Authors
Yong Deuk Kim; Yong-Hoon Kim; Tadi, Surendar; Ji Hoon Yu; Yong-Hyeon Yim; Nam Ho Jeoung; Minho Shong; Hennighausen, Lothar; Harris, Robert A.; In-Kyu Lee; Chul-Ho Lee; Hueng-Sik Choi
- Abstract
Growth hormone (GH) is a counter-regulatory hormone that plays an important role in preventing hypoglycemia during fasting. Because inhibition of the pyruvate dehydrogenase complex (PDC) by pyruvate dehydrogenase kinase 4 (PDK4) conserves substrates for gluconeogenesis, we tested whether GH increases PDK4 expression in liver by a signaling pathway sensitive to inhibition by metformin. The effects of GH and metformin were determined in the liver of wild-type, small heterodimer partner (SHP)-, PDK4-, and signal transducer and activator of transcription 5 (STAT5)-null mice. Administration of GH in vivo increased PDK4 expression via a pathway dependent on STAT5 phosphorylation. Metformin inhibited the induction of PDK4 expression by GH via a pathway dependent on AMP-activated protein kinase (AMPK) and SHP induction. The increase in PDK4 expression and PDC phosphorylation by GH was reduced in STAT5-null mice. Metformin decreased GH-mediated induction of PDK4 expression and metabolites in wildtype but not in SHP-null mice. In primary hepatocytes, dominant-negative mutant-AMPK and SHP knockdown prevented the inhibitory effect of metformin on GH-stimulated PDK4 expression. SHP directly inhibited STAT5 association on the PDK4 gene promoter. Metformin inhibits GH-induced PDK4 expression and metabolites via an AMPK-SHP--dependent pathway. The metformin-AMPK-SHP network may provide a novel therapeutic approach for the treatment of hepatic metabolic disorders induced by the GH-mediated pathway.
- Subjects
DIABETES; METFORMIN; SOMATOTROPIN; GENE expression; NUCLEAR receptors (Biochemistry)
- Publication
Diabetes, 2012, Vol 61, Issue 10, p2484
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db11-1665