Carcinogenesis, Vol. 20, No. 11, 2095-2100,
November 1999
© 1999 Oxford University Press
Cancer Biology |
Corn oil rapidly activates nuclear factor-
B in hepatic Kupffer cells by oxidant-dependent mechanisms
1 Curriculum in Toxicology,
2 Laboratory of Hepatobiology and Toxicology,
Department of Pharmacology,
3 Department of Medicine and
4 Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599-7365, USA
N-6 polyunsaturated fatty acids (N-6 PUFAs), major constituents of corn oil and natural ligands for peroxisome proliferator-activated receptors, increase the rate of growth of established tumors. It has been proposed that chemical peroxisome proliferators increase hepatocyte proliferation by mechanisms involving activation of nuclear factor-
B (NF-B) and production of low levels of tumor necrosis factor 
(TNF) by Kupffer cells; 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-B was tested. A single dose of corn oil (2 ml/kg, i.g.), but not olive oil or medium-chain triglycerides (saturated fat), caused an ~3-fold increase in hepatocyte proliferation. Similarly, when activity of NF-B in whole rat liver or isolated hepatocytes and Kupffer cells was measured at various time intervals for up to 36 h, only corn oil activated NF-B. Corn oil increased NF-B activity ~3-fold 1–2 h after treatment exclusively in the Kupffer cell fraction. In contrast, increases were small and only occurred after ~8 h in hepatocytes. The activation of NF-B at 2 h and increases in cell proliferation at 24 h due to corn oil were prevented almost completely when rats were pretreated for 4 days with either dietary glycine (5% w/w), an agent that inactivates Kupffer cells, or the NADPH oxidase inhibitor, diphenyleneiodonium (s.c., 1 mg/kg/day). Furthermore, arachidonic acid (100 µM) activated superoxide production ~4-fold when added to isolated Kupffer cells in vitro. This phenomenon was not observed with oleic or linoleic acids. Interestingly, a single dose of corn oil increased TNF mRNA nearly 2-fold 8 h after treatment. It is concluded that corn oil rapidly activates NF-B in Kupffer cells via oxidant-dependent mechanisms. This triggers production of low levels of TNF which is mitogenic in liver and promotes growth of hepatocytes.
Abbreviations: BrdU, 5-bromo-2'deoxyuridine; DPI, diphenyleneiodonium; MCT, medium chain triglycerides; N-6 PUFAs, N-6 polyunsaturated fatty acids; NF-B, nuclear factor-B; PKC, protein kinase C; PPARs, peroxisome proliferator activated receptors.
5 To whom correspondence should be addressed Email: iir{at}med.unc.edu
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