Peroxisome proliferator-activated receptor-beta/delta protects against chemically induced liver toxicity in mice.

Potential functional roles for the peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) in skeletal muscle fatty acid catabolism and epithelial carcinogenesis have recently been described. Whereas PPARbeta/delta is expressed in liver, its function in this tissue is less clear. To determine the role of PPARbeta/delta in chemically induced liver toxicity, wild-type and PPARbeta/delta-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 PPARbeta/delta-null mice, and these effects were not observed in similarly treated wild-type mice. Exacerbated carbon tetrachloride (CCl(4)) hepatoxicity was also observed in PPARbeta/delta-null as compared with wild-type mice. No differences in messenger RNAs (mRNAs) encoding cytochrome2E1 required for the metabolic activation of AOM and CCl(4) were observed between wild-type or PPARbeta/delta-null mice in response to CCl(4). Significant differences in the expression of genes reflecting enhanced nuclear factor kappa B (NF-kappaB) activity were noted in PPARbeta/delta-null mice. Results from these studies show that PPARbeta/delta is protective against liver toxicity induced by AOM and CCl(4), suggesting that this receptor is hepatoprotective against environmental chemicals that are metabolized in this tissue.