The mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis are not understood. Because of the uncertainty of human
cancer risk associated with
peroxisome proliferators, delineating the mechanisms of
carcinogenesis by these agents is of great interest. Alterations in liver
growth factors were postulated to contribute to the carcinogenic effect of
peroxisome proliferators. Administration of these compounds to rodents results in down-regulation of
hepatocyte growth factor (HGF) and supplementing culture medium with HGF is reported to suppress cell proliferation of preneoplastic and neoplastic cells from WY-14,643-treated livers. Combined, these observations suggest that reduced levels of hepatic HGF contribute to the mechanisms underlying peroxisome proliferator-induced hepatocarcinogenesis. To determine if HGF can prevent the effects of
peroxisome proliferators in liver, the short-term influence of
WY-14,643 in two different lines of HGF transgenic mice was examined. Mice were fed either a control diet or one containing 0.1% WY-14-643 for one week.
Hepatomegaly was found in both HGF transgenic mouse lines fed
WY-14,643 compared with controls. Additionally, hepatic expression of typical
mRNA markers of peroxisome proliferation including those encoding peroxisomal
fatty acid metabolizing
enzymes and cell cycle control
proteins were all significantly elevated in HGF transgenic mice fed
WY-14,643 compared with controls. Down-regulation of HGF was found to be dependent on
PPARalpha since lower levels of HGF
mRNA and
protein were observed in wild-type mice fed
WY-14,643 for 1 week and not in similarly treated
PPARalpha-null mice. These results demonstrate that the early increase in hepatic mRNAs associated with peroxisome and cell proliferation induced by
WY-14,643 treatment can not be prevented by overexpression of HGF in vivo.