TY - JOUR
T1 - Role of peroxisome proliferator-activated receptor-α (PPARα) in bezafibrate-induced hepatocarcinogenesis and cholestasis
AU - Hays, Thomas
AU - Rusyn, Ivan
AU - Burns, Amanda M.
AU - Kennett, Mary J.
AU - Ward, Jerrold M.
AU - Gonzalez, Frank J.
AU - Peters, Jeffrey M.
N1 - Funding Information:
The authors gratefully acknowledge Debra Wolgemuth, Christopher Sinal and Grace Guo for providing the cDNA probes. This work supported in part by CA89607 and CA97999 (J.M.P.).
PY - 2005/1
Y1 - 2005/1
N2 - 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.
AB - 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.
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U2 - 10.1093/carcin/bgh285
DO - 10.1093/carcin/bgh285
M3 - Article
C2 - 15447978
AN - SCOPUS:13444311098
SN - 0143-3334
VL - 26
SP - 219
EP - 227
JO - Carcinogenesis
JF - Carcinogenesis
IS - 1
ER -
