biostudies-literatureUnknown119(10)Leuenberger NAs most metabolic studies are conducted in male animals, understanding the sex specificity of the underlying molecular pathways has been broadly neglected; for example, whether PPARs elicit sex-dependent responses has not been determined. Here we show that in mice, PPARalpha has broad female-dependent repressive actions on hepatic genes involved in steroid metabolism and immunity. In male mice, this effect was reproduced by the administration of a synthetic PPARalpha ligand. Using the steroid oxysterol 7alpha-hydroxylase cytochrome P4507b1 (Cyp7b1) gene as a model, we elucidated the molecular mechanism of this sex-specific PPARalpha-dependent repression. Initial sumoylation of the ligand-binding domain of PPARalpha triggered the interaction of PPARalpha with GA-binding protein alpha (GABPaThe Journal of clinical investigation3138-48https://www.ebi.ac.uk/biostudies/studies/S-EPMC2752075biostudies-literatureSumoylated PPARalpha mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice.PMC2752075Wahli WLeuenberger NPradervand SfalseSumoylated PPARalpha mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice.As most metabolic studies are conducted in male animals, understanding the sex specificity of the underlying molecular pathways has been broadly neglected; for example, whether PPARs elicit sex-dependent responses has not been determined. Here we show that in mice, PPARalpha has broad female-dependent repressive actions on hepatic genes involved in steroid metabolism and immunity. In male mice, this effect was reproduced by the administration of a synthetic PPARalpha ligand. Using the steroid oxysterol 7alpha-hydroxylase cytochrome P4507b1 (Cyp7b1) gene as a model, we elucidated the molecular mechanism of this sex-specific PPARalpha-dependent repression. Initial sumoylation of the ligand-binding domain of PPARalpha triggered the interaction of PPARalpha with GA-binding protein alpha (GABPa2009-01-01T00:00:00Z2009 Oct2026-05-03T18:39:37.22Z2019-03-27T00:25:19ZS-EPMC27520751972983510.1172/jci3901910.1172/JCI39019