Expression of the hydrogen peroxide-generating enzyme fatty acyl CoA oxidase activates NF-kappa B

Peroxisome proliferators are a class of hepatic carcinogens in rodents and have been proposed to act in part by increasing oxidative stress. Fatty acy l CoA oxidase (FAO), which is highly induced by peroxisome proliferators, i s the hydrogen peroxide-generating enzyme of the peroxisomal beta-oxidation pathway. We previously showed that the treatment of rats and mice with the perosisome proliferator ciprofibrate resulted in increased hepatic NF-kapp a B activity and suggested that this effect may be secondary to the action of H2O2-generating enzymes. To test this possibility directly, we have dete rmined whether transient overexpression of FAO, in the absence of peroxisom e proliferators, leads to NF-kappa B activation. Here, we show that FAO ove rexpression in Cos-1 cells, in the presence of an H2O2-generating substrate , can activate a NF-kappa B regulated reporter gene. Electrophoretic mobili ty shift assays further demonstrated that FAO expression increases nuclear NF-kappa B DNA binding activity in a dose-dependent manner. The antioxidant s vitamin E and catalase can inhibit this activation. These results indicat e that FAO mediates, at least in part, peroxisome proliferator-induced NF-k appa B activation.