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J. Biol. Chem., Vol. 282, Issue 41, 30143-30149, October 12, 2007

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Epigallocatechin-3-gallate (EGCG), A Green Tea Polyphenol, Suppresses Hepatic Gluconeogenesis through 5'-AMP-activated Protein Kinase^*

Qu Fan Collins, Hui-Yu Liu, Jingbo Pi, Zhenqi Liu, Michael J. Quon^¶, and Wenhong Cao^||1

From the Translational Biology, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, the Division of Endocrinology, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, the ^¶Diabetes Unit, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, Maryland 20892-1755, and the ^||Division of Endocrinology, Department of Internal Medicine, Duke University, Medical Center, Durham, North Carolina 27710

Epigallocatechin-3-gallate (EGCG), a main catechin of green tea, has been suggested to inhibit hepatic gluconeogenesis. However, the exact role and related mechanism have not been established. In this study, we examined the role of EGCG in hepatic gluconeogenesis at concentrations that are reachable by ingestion of pure EGCG or green tea, and are not toxic to hepatocytes. Our results show in isolated hepatocytes that EGCG at relatively low concentrations (1 µM) inhibited glucose production via gluconeogenesis and expression of key gluconeogenic genes. EGCG was not toxic at these concentrations while demonstrating significant cytotoxicity at 10 µM and higher concentrations. EGCG at 1 µM or lower concentrations effective in suppressing hepatic gluconeogenesis did not activate the insulin signaling pathway, but activated 5'-AMP-activated protein kinase (AMPK). The EGCG suppression of hepatic gluconeogenesis was prevented by blockade of AMPK activity. In defining the mechanism by which EGCG activates AMPK, we found that the EGCG activation of AMPK was mediated by the Ca²⁺/calmodulin-dependent protein kinase kinase (CaMKK). Furthermore, our results show that the EGCG activation of AMPK and EGCG suppression of hepatic gluconeogenesis were both dependent on production of reactive oxygen species (ROS), which was a known activator of CaMKK. Together, our results demonstrate an inhibitory role for EGCG in hepatic gluconeogenesis and shed new light on the mechanism by which EGCG suppresses gluconeogenesis.

Received for publication, March 20, 2007 , and in revised form, August 9, 2007.

^* This study was supported by the Development Fund from the Hamner Institutes for Health Sciences (to W. C.), American Heart Association (SDG-0530244N) (to W. C.), and National Institutes of Health (R01DK076039) (to W. C.). 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.

¹ To whom correspondence should be addressed: The Hamner Institutes for Health Sciences, Six Davis Dr., P.O. Box 12137, Research Triangle Park, NC 27709. E-mail: wcao{at}thehamner.org.

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