Potential functional roles for the peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in skeletal muscle fatty acid catabolism and epithelial carcinogenesis have recently been described. Whereas PPARβ/δ is expressed in liver, its function in this tissue is less clear. To determine the role of PPARβ/δ in chemically induced liver toxicity, wild-type and PPARβ/δ-null mice were treated with azoxymethane (AOM) and markers of liver toxicity examined. Bile duct hyperplasia, regenerative hyperplasia, and increased serum alanine aminotransferase (ALT) were found in AOM-treated PPARβ/δ-null mice, and these effects were not observed in similarly treated wild-type mice. Exacerbated carbon tetrachloride (CCl4) hepatoxicity was also observed in PPARβ/δ-null as compared with wild-type mice. No differences in messenger RNAs (mRNAs) encoding cytochrome2E1 required for the metabolic activation of AOM and CCl4 were observed between wild-type or PPARβ/δ-null mice in response to CCl4. Significant differences in the expression of genes reflecting enhanced nuclear factor kappa B (NF-κB) activity were noted in PPARβ/δ-null mice. Conclusion: Results from these studies show that PPARβ/δ is protective against liver toxicity induced by AOM and CCl4, suggesting that this receptor is hepatoprotective against environmental chemicals that are metabolized in this tissue.
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