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J. Biol. Chem., Vol. 279, Issue 46, 47898-47905, November 12, 2004

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AMP-activated Protein Kinase Is Required for the Lipid-lowering Effect of Metformin in Insulin-resistant Human HepG2 Cells^*

Mengwei Zang, Adriana Zuccollo, Xiuyun Hou, Daisuke Nagata, Kenneth Walsh, Haya Herscovitz¶, Peter Brecher, Neil B. Ruderman||, and Richard A. Cohen**

From the Vascular Biology Unit, Whitaker Cardiovascular Institute, ^||Diabetes and Metabolism Unit, Department of Medicine, and the ^¶Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118

The antidiabetic drug metformin stimulates AMP-activated protein kinase (AMPK) activity in the liver and in skeletal muscle. To better understand the role of AMPK in the regulation of hepatic lipids, we studied the effect of metformin on AMPK and its downstream effector, acetyl-CoA carboxylase (ACC), as well as on lipid content in cultured human hepatoma HepG2 cells. Metformin increased Thr-172 phosphorylation of the subunit of AMPK in a dose- and time-dependent manner. In parallel, phosphorylation of ACC at Ser-79 was increased, which was consistent with decreasing ACC activity. Intracellular triacylglycerol and cholesterol contents were also decreased. These effects of metformin were mimicked or completely abrogated by adenoviral-mediated expression of a constitutively active AMPK or a kinase-inactive AMPK, respectively. An insulin-resistant state was induced by exposing cells to 30 mM glucose as indicated by decreased phosphorylation of Akt and its downstream effector, glycogen synthase kinase 3/. Under these conditions, the phosphorylation of AMPK and ACC was also decreased, and the level of hepatocellular triacylglycerols increased. The inhibition of AMPK and the accumulation of lipids caused by high glucose concentrations were prevented either by metformin or by expressing the constitutively active AMPK. The kinase-inactive AMPK increased lipid content and blocked the ability of metformin to decrease lipid accumulation caused by high glucose concentrations. Taken together, these results indicate that AMPK negatively regulates ACC activity and hepatic lipid content. Inhibition of AMPK may contribute to lipid accumulation induced by high concentrations of glucose associated with insulin resistance. Metformin lowers hepatic lipid content by activating AMPK, thereby mediating beneficial effects in hyperglycemia and insulin resistance.

Received for publication, July 19, 2004 , and in revised form, September 7, 2004.

^* This work was supported by National Institutes of Health Grants P01 HL68758 (to M. Z., N. B. R., and R. A. C.) and AR40197 (to D. N. and K. W.) and by a Strategic Alliance with Institut de Recherches Servier. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Vascular Biology Unit, X708, Boston University School of Medicine, 650 Albany St., Boston, MA 02118-2393. Tel.: 617-638-7115; Fax: 617-638-7113; E-mail: racohen{at}bu.edu.

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