Sumoylated PPARα 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, PPAR alpha 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 PPAR alpha ligand. Using the steroid oxysterol 7 alpha-hydroxylase cytochrome P450 7b1 (Cyp7b1) gene as a model, we elucidated the molecular mechanism of this sex-specific PPAR alpha-dependent repression. Initial sumoylation of the ligand-binding domain of PPAR alpha triggered the interaction of PPAR alpha with GA-binding protein alpha (GABP alpha) bound to the target Cyp7b1 promoter. Histone deacetylase and DNA and histone methylases were then recruited, and the adjacent Sp1-binding site and histones were methylated. These events resulted in loss of Sp1-stimulated expression and thus downregulation of Cyp7b1. Physiologically, this repression conferred on female mice protection against estrogen-induced intrahepatic cholestasis, the most common hepatic disease during pregnancy, suggesting a therapeutic target for prevention of this disease.