Sumoylated PPARα 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, PPARα 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 PPARα ligand. Using the steroid oxysterol 7α-hydroxylase cytochrome P450 7b1 (Cyp7b1) gene as a model, we elucidated the molecular mechanism of this sex-specific PPARα-dependent repression. Initial sumoylation of the ligand-binding domain of PPARα triggered the interaction of PPARα with GA-binding protein α (GABPα) 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.

Proline- and acidic amino acid-rich basic leucine zipper proteins modulate peroxisome proliferator-activated receptor α (PPARα) activity

“…Genome-wide microarray transcriptome profiling studies with liver RNA from wild-type and PAR bZip 3KO mice revealed differentially expressed genes involved in xenobiotic detoxification (9) and lipid metabolism (this paper). The latter included Pparα, a gene specifying a nuclear receptor that is well known as a regulator of lipid metabolism, and many PPARα target genes (10) (Fig. S1A).…”

Transcriptome analyses demonstrate that Peroxisome Proliferator-Activated Receptor α (PPARα) activity of an ultraviolet absorber, 2-(2’-hydroxy-3’,5’-di-tert-butylphenyl)benzotriazole, as possible mechanism of their toxicity and the gender differences

“…Recently, Leuenberger et al (2009) and Montagner et al (2011) compared hepatic mRNA expression profiles between wild-type mice and PPARα-null mice of each sex. The presence of PPARα stimulated a similar number of genes in males and females, but only half of the genes were upregulated by PPARα in common to both sexes.…”

“…The liver, the primary target organ of HDBB, is a sexually dimorphic organ (Leuenberger et al, 2009;Montagner et al, 2011). In mammals, more than 1600 hepatic genes are differentially expressed between males and females, and many of them are regulated by differences in pituitary growth hormone secretion, which is pulsatile in males and continuous in females.…”

Epigenetic regulation of oxysterol formation

“…Shafaati et al reported that in the SH-SY5Y cell system, CYP7B1 expression was suppressed by HDAC treatment [13]. Subsequently, the study of Leuenberger et al reported that HDAC inhibitor treatment led to an increase in CYP7B1 expression in HepG2 hepatoma cells and that silencing of HDAC1 and HDAC3 activated CYP7B1 in this cell system [51]. Thus while the available evidence is relatively limited, the consistent pattern of results in both the human prostate and mouse liver indicates that both methylation of DNA and/or proteins and histone acetylation are likely to be of importance for the regulation of the expression of CYP7B1.…”

“…In an elegant study, Leuenberger et al explored the mechanistic basis for the sexually dimorphic expression and provided evidence that methylation was critical for this to occur [51]. Post 15 translational sumoylation of the peroxisome proliferator-activated receptor-α (Pparα) increases interaction with GA-binding protein (Gabp) and leads to recruitment of HDAC and DNMT, ultimately leading to methylation of CpG residues within a key SP1 site and the trimethylation of lysine 9 of histone H3.…”