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

Détails

ID Serval
serval:BIB_09D2CA4DF67C
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Sumoylated PPARalpha mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice.
Périodique
Journal of Clinical Investigation
Auteur(s)
Leuenberger N., Pradervand S., Wahli W.
ISSN
1558-8238[electronic], 0021-9738[linking]
Statut éditorial
Publié
Date de publication
2009
Volume
119
Numéro
10
Pages
3138-3148
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
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.
Mots-clé
Amino Acid Motifs, Animals, Cholestasis, Intrahepatic/chemically induced, Cholestasis, Intrahepatic/prevention & control, Complement Activation, 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, Promoter Regions, Genetic, Sex Characteristics, Small Ubiquitin-Related Modifier Proteins/metabolism, Steroid Hydroxylases/genetics, Steroids/biosynthesis, Steroids/metabolism, Ubiquitination, Up-Regulation
Pubmed
Web of science
Création de la notice
18/11/2009 13:42
Dernière modification de la notice
20/08/2019 13:31
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