Resveratrol Increases Hepatic SHBG Expression through Human Constitutive Androstane Receptor: a new Contribution to the French Paradox

Cristina Saez-Lopez,J Torres-Torronteras,Laura Brianso-Llort,Rafael Simó,Geoffrey L Hammond,David M Selva

doi:10.1038/s41598-017-12509-x

Abstract

Sex hormone-binding globulin (SHBG) carries sex steroids in blood regulating their bioavailability. Red wine consumption increases plasma SHBG levels, and we have discovered that resveratrol, a polyphenol enriched in red wine, acts specifically through the human constitutive androstane receptor (CAR), a drug/xenobiotic detoxification gene regulator, to increase hepatic SHBG production. Chromatin immunoprecipitation and luciferase reporter gene assays show that human CAR binds to a typical direct repeat 1 nuclear hormone receptor-binding element in the human SHBG proximal promoter. Resveratrol also increased hepatic SHBG production in humanized SHBG/CAR transgenic mice. Moreover, SHBG expression correlated significantly with CAR mRNA levels in human liver biopsies. We conclude that the beneficial effects of red wine on the metabolic syndrome and it associated co-morbidities, including cardiovascular disease and type 2 diabetes, may be mediated in part by resveratrol acting via CAR to increase plasma SHBG levels.

Highlights

Sex hormone-binding globulin (SHBG) carries sex steroids in blood regulating their bioavailability
Human 18 S (h18S) rRNA was amplified as a control
It is important to mention that diluted red wine with an amount of resveratrol at the nM range it was more effective in increasing SHBG production in HepG2 cells than pure resveratrol at μM range

Summary

Introduction

Sex hormone-binding globulin (SHBG) carries sex steroids in blood regulating their bioavailability. We conclude that the beneficial effects of red wine on the metabolic syndrome and it associated co-morbidities, including cardiovascular disease and type 2 diabetes, may be mediated in part by resveratrol acting via CAR to increase plasma SHBG levels. Experiments in which the addition of red wine to culture medium increased SHBG production by human HepG2 liver cells led us to discover that resveratrol was responsible for this effect through a specific interaction with human CAR binding to a DR-1 element in the SHBG promoter. We found that SHBG mRNA levels correlated positively with CAR in human liver biopsies These findings provide mechanistic insight into the beneficial health effects of resveratrol and how it might contribute to reducing risk for the metabolic syndrome and its associated comorbidities

Methods

Results

Conclusion