Peroxisome proliferator-activated receptor α is restricted to hepatic parenchymal cells, not Kupffer cells:: implications for the mechanism of action of peroxisome proliferators in hepatocarcinogenesis

Peroxisome proliferators increase hepatocyte proliferation and cause liver tumors in rodents, yet the mechanism of action is not understood. Based on studies with null mice it is known that peroxisome proliferator-activated receptor-alpha (PPAR alpha) is involved. There is also evidence that Kupffer cells play a central role in peroxisome proliferator-induced carcinogenesis, most likely via mechanisms involving increases in superoxide, activation of nuclear factor kappa B and production of tumor necrosis factor-alpha (TNF alpha), However, it is not known whether PPAR alpha is constitutively expressed in Kupffer cells. Therefore, the expression of PPAR isoforms in rat Kupffer and parenchymal cells was examined. Kupffer cells and hepatocytes of >99 % purity mere isolated from rats fed either a control diet or one containing 0.1% WY-14,643 for 1 week. Protein and RNA were obtained and PPAR expression was analyzed using northern and western blots. PPAR alpha, PPAR beta and PPAR gamma mRNA was detected in purified hepatocytes, In Kupffer cells, mRNA encoding PPAR gamma was present while transcripts for PPAR alpha and PPAR beta were not detected, Immunoblots were consistent with the results found by northern analysis. Moreover, when Kupffer cells from wild-type or PPAR alpha-null mice were treated with WY-14,643 in vitro, superoxide production was similar. Combined, these results show that PPAR alpha is expressed in rat parenchymal cells but not in Kupffer cells. These data are consistent with the hypothesis that parenchymal cells respond to Kupffer cell-derived TNF alpha via mechanisms dependent on PPARa within the parenchymal cells.