Peroxisome proliferator-activated receptor alpha 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 r eceptor-alpha (PPAR alpha) is involved. There is also evidence that Kupffer cells play a central role in peroxisome proliferator-induced carcinogenesi s, most likely via mechanisms involving increases in superoxide, activation of nuclear factor kappa B and production of tumor necrosis factor-alpha (T NF alpha), However, it is not known whether PPAR alpha is constitutively ex pressed 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 co ntaining 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 c ells, mRNA encoding PPAR gamma was present while transcripts for PPAR alpha and PPAR beta were not detected, Immunoblots were consistent with the resu lts 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 p roduction was similar. Combined, these results show that PPAR alpha is expr essed in rat parenchymal cells but not in Kupffer cells. These data are con sistent with the hypothesis that parenchymal cells respond to Kupffer cell- derived TNF alpha via mechanisms dependent on PPARa within the parenchymal cells.