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

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

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

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Unterman, Terry G. Dimova, Elitsa Y. Kietzmann, Thomas Ganjam, Goutham Kumar
Description	Author Affiliation: Ganjam GK ( Faculty of Chemistry, Department of Biochemistry, University of Kaiserslautern, D-67663 Kaiserslautern, Germany.)
Abstract	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.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	45
Volume Number	284
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2009-11-06
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Forkhead Transcription Factors Metabolism Gene Expression Regulation, Enzymologic Drug Effects Glucokinase Genetics Hepatocyte Nuclear Factor 4 Liver Enzymology Stilbenes Pharmacology Animals Cells, Cultured Down-Regulation Hepatocytes Promoter Regions, Genetic Protein Binding Rats, Wistar Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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