%0 Journal Article
%T Hepatocellular proliferation in response to agonists of peroxisome proliferator-activated receptor alpha: a role for kupffer cells?
%A Alsarra Ibrahim A
%A Brockmann William G
%A Cunningham Michael L
%A Badr Mostafa Z
%J Journal of Carcinogenesis
%D 2006
%I Medknow Publications
%R 10.1186/1477-3163-5-26
%X Background It has been proposed that PPAR¦Á agonists stimulate Kupffer cells in rodents which in turn, release mitogenic factors leading to hepatic hyperplasia, and eventually cancer. However, Kupffer cells do not express PPAR¦Á receptors, and PPAR¦Á agonists stimulate hepatocellular proliferation in both TNF¦Á- and TNF¦Á receptor-null mice, casting doubt on the involvement of Kupffer cells in the mitogenic response to PPAR¦Á agonists. This study was therefore designed to investigate whether the PPAR¦Á agonist PFOA and the Kupffer cell inhibitor methylpalmitate produce opposing effects on hepatocellular proliferation and Kupffer cell activity in vivo, in a manner that would implicate these cells in the mitogenic effects of PPAR¦Á agonists. Methods Male Sprague-Dawley rats were treated intravenously via the tail vein with methylpalmitate 24 hrs prior to perfluorooctanoic acid (PFOA), and were sacrificed 24 hrs later, one hr after an intraperitoneal injection of bromodeoxyuridine (BrdU). Sera were analyzed for TNF¦Á and IL-1¦Â. Liver sections were stained immunohistochemically and quantified for BrdU incorporated into DNA. Results Data show that PFOA remarkably stimulated hepatocellular proliferation in the absence of significant changes in the serum levels of either TNF¦Á or IL-1¦Â. In addition, methylpalmitate did not alter the levels of these mitogens in PFOA-treated animals, despite the fact that it significantly blocked the hepatocellular proliferative effect of PFOA. Correlation between hepatocellular proliferation and serum levels of TNF¦Á or IL-1¦Â was extremely poor. Conclusion It is unlikely that mechanisms involving Kupffer cells play an eminent role in the hepatic hyperplasia, and consequently hepatocarcinogenicity attributed to PPAR¦Á agonists. This conclusion is based on the above mentioned published data and the current findings showing animals treated with PFOA alone or in combination with methylpalmitate to have similar levels of serum TNF¦Á and IL-1¦Â, which are reliable indicators of Kupffer cell activity, despite a remarkable difference in hepatocellular proliferation.
%U http://www.carcinogenesis.com/content/5/1/26