The Role of NF-kappaB in PPARalpha-Mediated Hepatocarcinogenesis

In this review, the role of NF-kappaB in the induction of hepatocarcinogenesis by peroxisome proliferators is examined. The administration of peroxisome proliferators for more than a three-day period leads to the activation of NF-kappaB in the livers of rats and mice. On the other hand, peroxisome proliferator activated receptor-alpha (PPARalpha) activation in non-hepatic tissues can lead to the inhibition of NF-kappaB activation. Several lines of evidence support the hypothesis that the activation of NF-kappaB by peroxisome proliferators in the liver is mediated by oxidative stress. The role of NF-kappaB in peroxisome proliferator-induced hepatocarcinogenesis has been examined using NF-kappaB knockout models. Specifically, the induction of cell proliferation and the promotion of liver carcinogenesis are inhibited in mice lacking the p50 subunit of NF-kappaB. Overall, the activation of NF-kappaB appears to be important in the carcinogenic activity of peroxisome proliferators.