PPARalpha-dependent activation of cell cycle control and DNA repair genes in hepatic nonparenchymal cells.

Peroxisome proliferator-activated receptor-α (PPARα) mediates the diverse biological effects of peroxisome proliferator (PP) chemicals, including fatty acid catabolism, hepatomegaly, hepatocyte proliferation, and hepatocarcinogenesis in rodents. However, transgenic mice expressing a constitutively active PPARα in hepatocytes (VP16PPARα) do not develop hepatocellular carcinomas in spite of hepatocyte proliferation and hepatomegaly; this suggests that activation of genes in nonparenchymal cells may have a critical role in PP-induced carcinogenesis. VP16PPARα mice exhibited massive peroxisome proliferation and hepatomegaly as well as increased mortality upon Wy-14,643 treatment. Several genes involved in cell cycle or DNA damage repair, such as Chek1, Prkdc, Mcm, and Rad51, were significantly induced to a similar extent between wild-type and VP16PPARα mice after Wy-14,643 administration. This induction was completely abolished in Pparα-null mice, suggesting a PPARα-dependent pathway. These data revealed a DNA damage response signaling network as an early event upon PP treatment and provide novel putative mechanisms for PP-induced hepatocellular carcinoma.