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