University of Oulu

Goutham Kumar Ganjam, Elitsa Y. Dimova, Terry G. Unterman, Thomas Kietzmann (2009) FoxO1 and HNF-4 Are Involved in Regulation of Hepatic Glucokinase Gene Expression by Resveratrol. J. Biol. Chem. 2009 284: 30783-30797. doi:10.1074/jbc.M109.045260

FoxO1 and HNF-4 are involved in regulation of hepatic glucokinase gene expression by resveratrol

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Author: Kumar Ganjam, Goutham1,2; Dimova, Elitsa Y.1,3; Unterman, Terry G.4,5;
Organizations: 1Faculty of Chemistry, Department of Biochemistry, University of Kaiserslautern, D-67663 Kaiserslautern, Germany
2Department of Nutrient Physiology, Philipps University Marburg, Karl-von-Frisch-Strasse 8, D-35043 Marburg, Germany
3Department of Biochemistry, University of Oulu, P.O. Box 3000, FI-90014 Oulu, Finland
4Departments of Medicine and Physiology and Biophysics, University of Illinois College of Medicine at Chicago, Chicago, Illinois 60612
5Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.1 MB)
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Language: English
Published: American Society for Biochemistry and Molecular Biology, 2009
Publish Date: 2017-03-15


Resveratrol, a polyphenol derived from grapes, exerts important effects on glucose and lipid metabolism, yet detailed mechanisms mediating these effects remain unknown. The liver plays a central role in energy homeostasis, and glucokinase (GK) is a key enzyme involved in glucose utilization. Resveratrol activates SIRT1 (sirtuin 1), which promotes deacetylation of the forkhead transcription factor FoxO1. Previously, we reported that FoxO1 can suppress and that HNF-4 can stimulate GK expression in the liver. Here, we examined the role of FoxO1 and HNF-4 in mediating resveratrol effects on liver GK expression. Resveratrol suppressed hepatic GK expression in vivo and in isolated hepatocytes, and knocking down FoxO1 with shRNAs disrupted this effect. Reporter gene, gel shift, supershift assay, and chromatin immunoprecipitation studies show that FoxO1 binds to the GK promoter and that the interplay between FoxO1 and HNF-4 within the GK promoter is essential for mediating the effects of resveratrol. Resveratrol promotes deacetylation of FoxO1 and enhances its recruitment to the FoxO-binding element. Conversely, resveratrol suppresses recruitment of HNF-4 to its binding site, and knockdown of FoxO1 blocks this effect of resveratrol. Coprecipitation and chromatin immunoprecipitation studies show that resveratrol enhances interaction between FoxO1 and HNF-4, reduces binding of HNF-4 to its own site, and promotes its recruitment to the FoxO site in a FoxO1-dependent manner. These results provide the first evidence that resveratrol represses GK expression via FoxO1 and that the interaction between FoxO1 and HNF-4 contributes to these effects of resveratrol.

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Series: Journal of biological chemistry
ISSN: 0021-9258
ISSN-E: 1067-8816
ISSN-L: 0021-9258
Volume: 285
Issue: 45
Pages: 30783 - 30797
DOI: 10.1074/jbc.M109.045260
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Copyright information: © 2009 by The American Society for Biochemistry and Molecular Biology, Inc. Published in this repository with the kind permission of the publisher.