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Journal of Lipid Research, Vol. 47, 1281-1288, June 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine

Jean-Marie Brusq¹, Nicolas Ancellin, Pascal Grondin, Raphaelle Guillard, Sandrine Martin, Yannick Saintillan and Marc Issandou

GlaxoSmithKline, 91951 Les Ulis, Cedex, France

Published, JLR Papers in Press, February 28, 2006.

¹ To whom correspondence should be addressed. e-mail: jean-marie.g.brusq{at}gsk.com

The alkaloid drug berberine (BBR) was recently described to decrease plasma cholesterol and triglycerides (TGs) in hypercholesterolemic patients by increasing expression of the hepatic low density lipoprotein receptor (LDLR). Using HepG2 human hepatoma cells, we found that BBR inhibits cholesterol and TG synthesis in a similar manner to the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide 1-ß-ribofuranoside (AICAR). Significant increases in AMPK phosphorylation and AMPK activity were observed when the cells were incubated with BBR. Activation of AMPK was also demonstrated by measuring the phosphorylation of acetyl-CoA carboxylase, a substrate of AMPK, correlated with a subsequent increase in fatty acid oxidation. All of these effects were abolished by the mitogen-activated protein kinase kinase inhibitor PD98059. Treatment of hyperlipidemic hamsters with BBR decreased plasma LDL cholesterol and strongly reduced fat storage in the liver. These findings indicate that BBR, in addition to upregulating the LDLR, inhibits lipid synthesis in human hepatocytes through the activation of AMPK. These effects could account for the strong reduction of plasma TGs observed with this drug in clinical trials.

Supplementary key words low density lipoprotein cholesterol • PD98059 • 5-aminoimidazole-4-carboxamide 1-ß-ribofuranoside • fatty acid oxidation • phosphorylation of acetyl-coenzyme A carboxylase

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