Sumoylated 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 (GABPalpha) 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.
Leuenberger
Nicolas
N
Center for Integrative Genomics, National Research Center "Frontiers in Genetics," Switzerland.
Pradervand
Sylvain
S
Wahli
Walter
W
D020816:Amino Acid Motifs; D000818:Animals; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced / Q000517:prevention & control; D003167:Complement Activation; D000072474:Cytochrome P450 Family 7; D019175:DNA Methylation; D015536:Down-Regulation; D004794:Enzyme Repression; D004997:Ethinyl Estradiol / Q000633:toxicity*; D005260:Female; D051268:GA-Binding Protein Transcription Factor / Q000737:chemistry / Q000378:metabolism; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012727:Sex Characteristics; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics; D013256:Steroids / Q000096:biosynthesis / Q000378:metabolism; D054875:Ubiquitination; D015854:Up-Regulation
D051268:GA-Binding Protein Transcription Factor; D006657:Histones; D008024:Ligands; D047493:PPAR alpha; D025841:Small Ubiquitin-Related Modifier Proteins; D013256:Steroids; D004997:Ethinyl Estradiol; D013250:Steroid Hydroxylases; D000072474:Cytochrome P450 Family 7; C097207:Cyp7b1 protein, mouse