Journal Article

Corn oil rapidly activates nuclear factor-κB in hepatic Kupffer cells by oxidant-dependent mechanisms

Ivan Rusyn, Cynthia A. Bradham, Leslie Cohn, Robert Schoonhoven, James A. Swenberg, David A. Brenner and Ronald G. Thurman

in Carcinogenesis

Volume 20, issue 11, pages 2095-2100
Published in print November 1999 | ISSN: 0143-3334
Published online November 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.11.2095
Corn oil rapidly activates nuclear factor-κB in hepatic Kupffer cells by oxidant-dependent mechanisms

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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-κB (NF-κB) and production of low levels of tumor necrosis factor α (TNFα) 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-κB 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-κB 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-κB. Corn oil increased NF-κB 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-κB 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 TNFα mRNA nearly 2-fold 8 h after treatment. It is concluded that corn oil rapidly activates NF-κB in Kupffer cells via oxidant-dependent mechanisms. This triggers production of low levels of TNFα which is mitogenic in liver and promotes growth of hepatocytes.

Keywords: BrdU, 5-bromo-2′deoxyuridine; DPI, diphenyleneiodonium; MCT, medium chain triglycerides; N-6 PUFAs, N-6 polyunsaturated fatty acids; NF-κB, nuclear factor-κB; PKC, protein kinase C; PPARs, peroxisome proliferator activated receptors.

Journal Article.  5469 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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