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, Richard A. Cohen

Research output: Contribution to journalArticle

345 Scopus citations

Abstract

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 α 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 AMPKa or a kinase-inactive AMPKα, 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 3α/β. 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 AMPKα. The kinase-inactive AMPKD increased lipid content and blocked the ability of metformin to decrease lipid accumulation caused by high glucose concentrations. Taken together, these results indicate that AMPKa 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 hyperglycemic and insulin resistance.

Original languageEnglish (US)
Pages (from-to)47898-47905
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number46
DOIs
StatePublished - Nov 12 2004
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Zang, M., Zuccollo, A., Hou, X., Nagata, D., Walsh, K., Herscovitz, H., Brecher, P., Ruderman, N. B., & Cohen, R. A. (2004). AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. Journal of Biological Chemistry, 279(46), 47898-47905. https://doi.org/10.1074/jbc.M408149200