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.