Resveratrol increases hepatic SHBG expression through human constitutive androstane receptor: a new Contribution to the French Paradox

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.Sex hormone-binding globulin (SHBG) is produced and secreted by the human liver into the blood, where it binds androgens and estrogens with high affinity, regulating their bioavailability 1 . Low plasma SHBG levels are associated with obesity and the metabolic syndrome predicting risk for type 2 diabetes 2-5 and cardiovascular disease 4,6,7 . Studies of human SHBG regulation have revealed cis-acting elements in the human SHBG proximal promoter that interact with members of the nuclear hormone receptor (NHR) family, including HNF4α and COUP-TF that compete for an imperfect NHR DR-1 (direct repeat-1) element located about 20 bp upstream of the transcription start site, and act as the main stimulators and repressors of SHBG expression in liver cells, respectively 8 . In addition, PPARγ interacts with a consensus DR-1 element located about 50 bp further upstream, which also binds HNF4α and COUP-TF 8 , and PPARγ binding at this position represses SHBG transcription 9 . Olive oil and red wine are important components of the Mediterranean diet 10 that are associated with a decreased risk of cardiovascular disease [11][12][13][14] . We have shown that olive oil consumption is associated with elevated serum SHBG levels and that PPARγ downregulation induced by oleoyl-CoA is an underlying mediator of this effect 15 . Numerous epidemiological studies indicate that cardiovascular risk is decreased by moderate wine consumption, providing an explanation for the "French Paradox" [16][17][18][19] . The beneficial cardiovascular effects of wine consumption have been attributed to components other than alcohol [20][21][22] , which are generally referred to as congeners of alcoholic beverages. These include the polyphenols, and red wine contains between 5 and 20-fold higher concentrations of polyphenols than does white wine 23,24 . Among these polyphenols, resveratrol

Effect of Resveratrol Content in Red Wine on Circulating Sex Hormone‐Binding Globulin: Lessons from a Pilot Clinical Trial

“…Why the red wine high in resveratrol only increased plasma SHBG levels in women is intriguing and it merits further investigation in a different setting of experiments. We have previously reported using HepG2 cells and the humanized SHBG‐CAR transgenic mice [ 21 ] that resveratrol increases plasma SHBG levels through the constitutive androstane receptor (CAR). In this regard, a possible explanation for the sexual dimorphic response to resveratrol found in our pilot study could be influenced by the differences in expression of CAR between men and women and the different modulating action of sex steroids.…”

“…These studies allowed us to show that resveratrol increased hepatic SHBG production through the constitutive androstane receptor (CAR). [ 21 ]…”

Recent Advances on Sex Hormone‐Binding Globulin Regulation by Nutritional Factors: Clinical Implications

“…[45,[47][48][49][50][51][52] In a series of comprehensive experiments, we have shown that red wine and resveratrol increase SHBG production in HepG2 cells. [3] Mechanistically, resveratrol acts specifically through the human constitutive androstane receptor (CAR), a drug/xenobiotic detoxification gene regulator, [53][54][55][56] to increase hepatic SHBG production by binding to a DR-1 element, present in the footprint 3 region of the SHBG promoter. [3] These results were corroborated in vivo using a humanized SHBG/CAR transgenic mouse, where plasma SHBG levels were increased by resveratrol consumption.…”

“…[3] Mechanistically, resveratrol acts specifically through the human constitutive androstane receptor (CAR), a drug/xenobiotic detoxification gene regulator, [53][54][55][56] to increase hepatic SHBG production by binding to a DR-1 element, present in the footprint 3 region of the SHBG promoter. [3] These results were corroborated in vivo using a humanized SHBG/CAR transgenic mouse, where plasma SHBG levels were increased by resveratrol consumption. [3] Moreover, SHBG expression correlated significantly with CAR mRNA levels in human liver biopsies.…”

“…[2] • FP3 region: HNF-4𝛼, estrogen receptor alpha (ER𝛼), and constitutive androstane receptor (CAR) activate SHBG transcription, while peroxisome proliferator activated receptor gamma (PPAR𝛾) inhibits SHBG transcription. [2,3] • FP4 region: upstream stimulatory factor 1/2 (USF1/2) activates SHBG transcription. [4] 1.…”