Role of peroxisome proliferator-activated receptor-alpha (PPARalpha) in bezafibrate-induced hepatocarcinogenesis and cholestasis

Carcinogenesis. 2005 Jan;26(1):219-27. doi: 10.1093/carcin/bgh285. Epub 2004 Sep 24.

Abstract

Prolonged administration of peroxisome proliferators to rodents typically leads to hepatocarcinogenesis. Peroxisome proliferator-activated receptor-alpha (PPARalpha) is required to mediate alterations in PPARalpha target gene expression, repress apoptosis, enhance replicative DNA synthesis, oxidative stress to DNA and hepatocarcinogenesis induced by the relatively specific PPARalpha agonist, Wy-14,643. Interestingly, administration of the less specific PPARalpha agonist, bezafibrate, leads to a modest induction of PPARalpha target genes in the absence of PPARalpha expression. In these studies, the role of PPARalpha in modulating hepatocarcinogenesis induced by long-term feeding of 0.5% bezafibrate was examined in wild-type (+/+) and PPARalpha-null (-/-) mice. The average liver weight was significantly higher in (+/+) and (-/-) mice fed bezafibrate 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 PPARalpha is required to mediate hepatocarcinogenesis induced by bezafibrate, and that PPARalpha protects against potential cholestasis.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acyl-CoA Oxidase / drug effects
  • Acyl-CoA Oxidase / metabolism
  • Animals
  • Bezafibrate / metabolism*
  • Bezafibrate / toxicity
  • Bile Acids and Salts / metabolism
  • Blotting, Northern
  • Cell Cycle Proteins / drug effects
  • Cell Cycle Proteins / metabolism
  • Cholestasis / chemically induced*
  • Cholestasis / metabolism
  • Cholestasis / pathology
  • Cytochrome P-450 CYP4A / drug effects
  • Cytochrome P-450 CYP4A / metabolism
  • DNA Repair Enzymes / drug effects
  • DNA Repair Enzymes / metabolism
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • PPAR alpha / deficiency*
  • PPAR alpha / genetics
  • Peroxisome Proliferators / toxicity*
  • RNA, Messenger / analysis
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors / drug effects
  • Transcription Factors / metabolism

Substances

  • Bile Acids and Salts
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • PPAR alpha
  • Peroxisome Proliferators
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • farnesoid X-activated receptor
  • Cytochrome P-450 CYP4A
  • Acyl-CoA Oxidase
  • DNA Repair Enzymes
  • Bezafibrate