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

Abstract

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.

• Authors: Nicolas Leuenberger, Sylvain Pradervand, Walter Wahli
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 119 Issue 10 Pg. 3138-48 (Oct 2009) ISSN: 1558-8238 [Electronic] United States
• PMID: 19729835 (Publication Type: Journal Article)

Chemical References

• 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

Topics

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