Corn oil rapidly activates nuclear factor-kappa B in hepatic Kupffer cellsby oxidant-dependent mechanisms

N-6 polyunsaturated fatty acids (N-6 PUFAs), major constituents of corn oil and natural ligands for peroxisome proliferator-activated receptors, incre ase the rate of growth of established tumors, It has been proposed that che mical peroxisome proliferators increase hepatocyte proliferation by mechani sms involving activation of nuclear factor-kappa B (NF-kappa B) and product ion of low levels of tumor necrosis factor alpha (TNF alpha) by Kupffer cel ls; however, how N-6 PUFAs are involved in increased cell proliferation in liver is not well understood. Here, the hypothesis that N-6 PUFAs increase production of mitogens by activation of Kupffer cell NF-kappa B was tested, A single dose of corn oil (2 ml/kg, i.g.), but not olive oil or medium-cha in triglycerides (saturated fat), caused an similar to 3-fold increase in h epatocyte proliferation. Similarly, when activity of NF-kappa B in whole ra t liver or isolated hepatocytes and Kupffer cells was measured at various t ime intervals for up to 36 h, only corn oil activated NF-kappa B, Corn oil increased NF-kappa B activity similar to 3-fold 1-2 h after treatment exclu sively in the Kupffer cell fraction, In contrast, increases were small and only occurred after similar to 8 h in hepatocytes. The activation of NF-kap pa B at 2 h and increases in cell proliferation at 24 h due to corn oil wer e prevented almost completely when rats were pretreated for 4 days with eit her dietary glycine (5% w/w), an agent that inactivates Kupffer cells, or t he NADPH oxidase inhibitor, diphenyleneiodonium (s.c., 1 mg/kg/day), Furthe rmore, arachidonic acid (100 mu M) activated superoxide production similar to 4-fold when added to isolated Kupffer cells in vitro, This phenomenon wa s not observed with oleic or linoleic acids, Interestingly, a single dose o f corn oil increased TNF alpha mRNA nearly 2-fold 8 h after treatment. It i s concluded that corn oil rapidly activates NF-kappa B in Kupffer cells via oxidant-dependent mechanisms, This triggers production of low levels of TN F alpha which is mitogenic in liver and promotes growth of hepatocytes.