Regulation of hepatic gluconeogenic gene expression by resveratrol

Abstract

[한글]

[영문]

Resveratrol, a naturally occurring polyphenol found in grape and red wine,is known as an activator of silent information regulator 2 (Sir2), which is anNAD+-dependent histone deacetylase. Sir2 induces longevity inSaccharomyces cerevisiae and Caenorhabditis elegans in response to caloricrestriction. SIRT1, one of the seven mammalian homologues (sirtuins) ofSir2 family, is responsible for the regulation of diverse energy metabolism.One of transcription factors regulating energy metabolism, the forkheadtranscription factor (FOXO1), is known as a transcriptional activator of genes involved in the gluconeogenesis. In the presence of insulin, FOXO1 isphosphorylated and exported from nucleus to cytosol, losing its ability toactivate gene transcription.This study is designed to explore the molecular mechanism of resveratol,an activator of SIRT1, with regard to insulin action on the transcriptionalcontrol of gluconeogenic genes. Resveratrol inhibited phosphorylation ofPI3K/AKT and ERK 1/2. Sirtinol, an inhibitor of SIRT1, treatment restoredresveratrol-induced inhibition of insulin response. Immunofluorescencemicroscopy revealed that FOXO1 is distributed in the nucleus by resveratroltreatment, even in the presence of insulin. Chromatin immunoprecipitation(ChIP) assay using nuclear extract showed that FOXO1 binding to the insulinresponsive element (IRE) in the promoter region of gluconeogenic genes isincreased by resveratrol treatment.These results suggest that resveratrol upregulates the expression ofgluconeogenic genes by either attenuating insulin signaling or increasingFOXO1 binding to the IRE.