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

Carcinogenesis. 1999 Nov;20(11):2095-100. doi: 10.1093/carcin/20.11.2095.

Abstract

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-kappaB (NF-kappaB) and production of low levels of tumor necrosis factor alpha (TNFalpha) 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-kappaB 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 approximately 3-fold increase in hepatocyte proliferation. Similarly, when activity of NF-kappaB 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-kappaB. Corn oil increased NF-kappaB activity approximately 3-fold 1-2 h after treatment exclusively in the Kupffer cell fraction. In contrast, increases were small and only occurred after approximately 8 h in hepatocytes. The activation of NF-kappaB 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 microM) activated superoxide production approximately 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 TNFalpha mRNA nearly 2-fold 8 h after treatment. It is concluded that corn oil rapidly activates NF-kappaB in Kupffer cells via oxidant-dependent mechanisms. This triggers production of low levels of TNFalpha which is mitogenic in liver and promotes growth of hepatocytes.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Division / drug effects
  • Cells, Cultured
  • Corn Oil / pharmacology*
  • Female
  • Kupffer Cells / drug effects*
  • Kupffer Cells / metabolism
  • Liver / cytology
  • Liver / drug effects*
  • Liver / metabolism
  • NF-kappa B / metabolism*
  • Oxidants / pharmacology*
  • Pyrimidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • NF-kappa B
  • Oxidants
  • Pyrimidines
  • Tumor Necrosis Factor-alpha
  • Corn Oil
  • pirinixic acid