Evidence that reduction of hepatocyte growth factor (HGF) is not required for peroxisome proliferator-induced hepatocyte proliferation

The mechanisms underlying peroxisome proliferator-induced hepatocarcinogene sis are not understood, Because of the uncertainty of human cancer risk ass ociated with peroxisome proliferators, delineating the mechanisms of carcin ogenesis by these agents is of great interest. Alterations in liver growth factors were postulated to contribute to the carcinogenic effect of peroxis ome 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 preneoplasti c and neoplastic cells from WY-14,643-treated livers, Combined, these obser vations suggest that reduced levels of hepatic HGF contribute to the mechan isms underlying peroxisome proliferator-induced hepatocarcinogenesis. To de termine 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 trans genic mice was examined, Mice were fed either a control diet or one contain ing 0.1% WY-14-643 for one week. Hepatomegaly was found in both HGF transge nic mouse lines fed WY-14,643 compared with controls. Additionally, hepatic expression of typical mRNA markers of peroxisome proliferation including t hose encoding peroxisomal fatty acid metabolizing enzymes and cell cycle co ntrol proteins were all significantly elevated in HGF transgenic mice fed W Y-14,643 compared with controls. Down-regulation of HGF was found to be dep endent on PPAR alpha since lower levels of HGF mRNA and protein were observ ed in wild-type mice fed WY-14,643 for 1 week and not in similarly treated PPAR alpha -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.