摘要：

The objective of this study was to determine how the AMPK activating antidiabetic drug metformin affects the major activator of hepatic gluconeogenesis, PPAR<IMG alt=[gamma] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b3.gif"> coactivator 1<IMG alt=[alpha] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b1.gif"> (PGC-1<IMG alt=[alpha] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b1.gif">) and liver functions regulated by PGC-1<IMG alt=[alpha] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b1.gif">.Experimental ApproachMouse and human primary hepatocytes and mice in vivo were treated with metformin. Adenoviral overexpression, siRNA and reporter gene constructs were used for mechanistic studies.Key ResultsMetformin increased PGC-1<IMG alt=[alpha] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b1.gif"> mRNA and protein expression in mouse primary hepatocytes. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) (another AMPK activator) had the opposite effect. Metformin also increased PGC-1<IMG alt=[alpha] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b1.gif"> in human primary hepatocytes; this effect of metformin was abolished by AMPK inhibitor compound C and sirtuin 1 siRNA. AMPK overexpression by AMPK-Ad also increased PGC-1<IMG alt=[alpha] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b1.gif">. Whereas metformin increased PGC-1<IMG alt=[alpha] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b1.gif">, it down-regulated gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). Furthermore, metformin attenuated the increase in PEPCK and G6Pase mRNAs induced by PGC-1<IMG alt=[alpha] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b1.gif"> overexpression, but did not affect PGC-1<IMG alt=[alpha] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b1.gif">-mediated induction of mitochondrial genes. Metformin down-regulated several key transcription factors that mediate the effect of PGC-1<IMG alt=[alpha] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b1.gif"> on gluconeogenic genes including Krüppel-like factor 15, forkhead box protein O1 and hepatocyte NF 4<IMG alt=[alpha] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b1.gif">, whereas it increased nuclear respiratory factor 1, which is involved in PGC-1<IMG alt=[alpha] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b1.gif">-mediated regulation of mitochondrial proteins.Conclusions and ImplicationsDown-regulation of PGC-1<IMG alt=[alpha] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b1.gif"> is not necessary for suppression of gluconeogenic genes by metformin. Importantly, metformin selectively affects hepatic PGC-1<IMG alt=[alpha] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b1.gif">-mediated gene regulation and prevents activation of gluconeogenesis, but does not influence its regulation of mitochondrial genes. These results identify selective modulation of hepatic PGC-1<IMG alt=[alpha] src="http://onlinelibrarystatic.wiley.com/undisplayable_characters/0003b1.gif"> functions as a novel mechanism involved in the therapeutic action of metformin.

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