PPARalpha: mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators.
Peroxisome proliferator chemicals are classic non-genotoxic carcinogens. These agents cause liver cancers when chronically administered to rats and mice. Peroxisome proliferators include the widely prescribed lipid and cholesterol lowering fibrate drugs. In contrast to the results in rodents, there is no evidence that fibrates are associated with elevated risk of liver cancer or any other neoplasms in humans thus indicating a species difference in the hepatocarcinogenic response. The biological effects of peroxisome proliferators are mediated by the peroxisome proliferator-activated receptor (PPAR)alpha. Pparalpha-null mice are resistant to all of the pleiotropic effects of peroxisome proliferators, including cell proliferation and hepatocarcinogenesis. The mechanism of hepatocellular proliferation involves downregulation of the microRNA let-7c gene by PPARalpha. Let-7c controls levels of proliferative c-myc by destabilizing its mRNA. Thus, upon suppression of let-7c, c-myc mRNA and protein are elevated resulting in enhanced hepatocellular proliferation. In contrast, PPARalpha-humanized mice, that respond to Wy-14,643 by lower serum triglycerides and induction of genes encoding fatty acid metabolizing enzymes, are resistant to peroxisome proliferator-induced cell proliferation and cancer. These mice do not exhibit downregulation of let-7c gene expression thus forming the basis for the resistance to hepatocellular carcinogenesis.
Gonzalez
Frank J
FJ
National Cancer Research, National Institutes of Health, Bethesda, MD 20892, USA. fjgonz@helix.nih.gov
Shah
Yatrik M
YM
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D047493:PPAR alpha / Q000235:genetics / Q000502:physiology / Q000633:toxicity*; D020025:Peroxisome Proliferators / Q000378:metabolism / Q000633:toxicity*; D011743:Pyrimidines / Q000378:metabolism / Q000633:toxicity*; D055291:Salivary alpha-Amylases; D013045:Species Specificity; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D014157:Transcription Factors; C006253:pirinixic acid; C524799:Amy1 protein, mouse; D055291:Salivary alpha-Amylases