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.


CONCLUSIONS
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.
Shan
Weiwei
W
Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Huck Institute of Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
Nicol
Christopher J
CJ
Ito
Shinji
S
Bility
Moses T
MT
Kennett
Mary J
MJ
Ward
Jerrold M
JM
Gonzalez
Frank J
FJ
Peters
Jeffrey M
JM
D000818:Animals; D001397:Azoxymethane / Q000506:poisoning; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism*; D002273:Carcinogens / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D047494:PPAR delta / Q000172:deficiency*; D048068:PPAR-beta / Q000172:deficiency*
D002273:Carcinogens; D016328:NF-kappa B; D047494:PPAR delta; D048068:PPAR-beta; D003577:Cytochrome P-450 Enzyme System; D001397:Azoxymethane