Sumoylated PPARalpha mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice

J Clin Invest. 2009 Oct;119(10):3138-48. doi: 10.1172/JCI39019.


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.

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Cholestasis, Intrahepatic / chemically induced
  • Cholestasis, Intrahepatic / prevention & control
  • Complement Activation
  • Cytochrome P450 Family 7
  • DNA Methylation
  • Down-Regulation*
  • Enzyme Repression
  • Ethinyl Estradiol / toxicity*
  • Female
  • GA-Binding Protein Transcription Factor / chemistry
  • GA-Binding Protein Transcription Factor / metabolism
  • Gene Expression Profiling
  • Histones / metabolism
  • Humans
  • Ligands
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Mice
  • Myocardium / metabolism
  • Oligonucleotide Array Sequence Analysis
  • PPAR alpha / chemistry
  • PPAR alpha / genetics
  • PPAR alpha / metabolism*
  • Promoter Regions, Genetic
  • Sex Characteristics*
  • Small Ubiquitin-Related Modifier Proteins / metabolism
  • Steroid Hydroxylases / genetics
  • Steroids / biosynthesis
  • Steroids / metabolism
  • Ubiquitination
  • Up-Regulation


  • GA-Binding Protein Transcription Factor
  • Histones
  • Ligands
  • PPAR alpha
  • Small Ubiquitin-Related Modifier Proteins
  • Steroids
  • Ethinyl Estradiol
  • Steroid Hydroxylases
  • Cytochrome P450 Family 7
  • Cyp7b1 protein, mouse