Sumoylated PPARα mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice
Nicolas Leuenberger, … , Sylvain Pradervand, Walter Wahli
Nicolas Leuenberger, … , Sylvain Pradervand, Walter Wahli
Published September 1, 2009
Citation Information: J Clin Invest. 2009;119(10):3138-3148. https://doi.org/10.1172/JCI39019.
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Research Article Genetics

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.

Authors

Nicolas Leuenberger, Sylvain Pradervand, Walter Wahli

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Figure 2

PPARα modulates hepatic steroid biosynthesis.

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PPARα modulates hepatic steroid biosynthesis. (A) Heat maps of selected ...
(A) Heat maps of selected gene sets significantly enriched in genes with sexual dimorphism in PPARα-null mice. The log2-fold differences between PPARα-null and WT female and male mice are presented; for each gene set, the color correspondence is indicated on the right. Genes are ordered in each set by significance of the change in expression in females, with the most significant on the left. Cholesterol biosynthesis, cholesterol biosynthesis canonical pathway; CR low liver up, upregulated in liver from mice with reduced liver expression of NADPH–cytochrome P450 reductase (CPR) versus normal controls; Comppathway, both the classic and alternative immune complement pathways that promote inflammation, foreign cell lysis, and phagocytosis. For data, see Supplemental Table 4. (B) Female PPARα-null (KO) and WT mice (n = 8 per group) were treated (black bars) or not treated (white bars) for 5 days with WY-14643. Plasma androstenedione and testosterone levels were determined. Values are mean ± SEM. *P ≤ 0.05, **P ≤ 0.01.