Role of peroxisome proliferator-activated receptor-α (PPARα) in bezafibrate-induced hepatocarcinogenesis and cholestasis

Thomas Hays, Ivan Rusyn, Amanda M. Burns, Mary J. Kennett, Jerrold M. Ward, Frank J. Gonzalez, Jeffrey M. Peters

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

Prolonged administration of peroxisome proliferators to rodents typically leads to hepatocarcinogenesis. Peroxisome proliferator-activated receptor-α (PPARα) is required to mediate alterations in PPARα target gene expression, repress apoptosis, enhance replicative DNA synthesis, oxidative stress to DNA and hepatocarcinogenesis induced by the relatively specific PPARα agonist, Wy-14,643. Interestingly, administration of the less specific PPARα agonist, bezafibrate, leads to a modest induction of PPARα target genes in the absence of PPARα expression. In these studies, the role of PPARα in modulating hepatocarcinogenesis induced by long-term feeding of 0.5% bezafibrate was examined in wild-type (+/+) and PPARα-null (-/-) mice. The average liver weight was significantly higher in (+/+) and (-/-) mice fed bezaribrate than controls, but this effect was considerably less in (-/-) mice as compared with similarly treated (+/+) mice. Increased levels of mRNA encoding cell cycle regulatory proteins and DNA repair enzymes were found in (+/+) mice fed bezafibrate, and this effect was not found in (-/-) mice. In mice fed bezafibrate for 1 year, preneoplastic foci, adenomas and a hepatocellular carcinoma were found in (+/+) mice, while only a single microscopic adenoma was found in one (-/-) mouse. This effect was observed in both Sv/129 and C57BL/6N strains of mice, although only preneoplastic foci were observed in the latter strain. Interestingly, hepatic cholestasis was observed in 100% of the bezafibrate-fed (-/-) mice, and this was accompanied by significantly elevated hepatic expression of mRNA encoding bile salt export pump and lower expression of mRNA encoding cytochrome P450 7A1, consistent with enhanced activation of the bile acid receptor, farnesoid X receptor. Results from these studies demonstrate that the PPARα is required to mediate hepatocarcinogenesis induced by bezafibrate, and that PPARα protects against potential cholestasis.

Original languageEnglish (US)
Pages (from-to)219-227
Number of pages9
JournalCarcinogenesis
Volume26
Issue number1
DOIs
StatePublished - Jan 2005

All Science Journal Classification (ASJC) codes

  • Cancer Research

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