A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA (PPAR-ALPHA) CDNA CLONED FROM GUINEA-PIG LIVER ENCODES A PROTEIN WITH SIMILAR PROPERTIESTO THE MOUSE PPAR-ALPHA - IMPLICATIONS FOR SPECIES-DIFFERENCES IN RESPONSES TO PEROXISOME PROLIFERATORS

The peroxisome proliferator class of non-genotoxic rodent hepatocarcin ogens cause hepatocyte DNA synthesis, peroxisome proliferation and liv er tumours when administered to rats and mice, but fail to induce S-ph ase or peroxisome proliferation in hepatocytes from other species incl uding guinea-pigs, dogs, and primates including humans. There are comp elling data that implicate a nuclear receptor, the peroxisome prolifer ator-activated receptor-alpha (PPAR alpha) as an important mediator of the toxic and carcinogenic effects of peroxisome proliferators (PPs). We were interested to consider the guinea-pig as a possible model for human responses to these compounds. This manuscript describes the iso lation of a full-length cDNA encoding PPAR alpha from guinea-pig liver that is closely related to receptors identified previously in mouse, rat and human. RNA hybridisation experiments suggested that the livers of the PP-responsive rat and mouse contained relatively high levels o f PPAR alpha transcripts, whereas in human and guinea-pig liver PPAR a lpha mRNA was much less abundant. Functional analyses suggested that t he guinea-pig PPAR alpha was able to be activated by PPs. DNA binding studies using in vitro translated proteins showed that the guinea-pig receptor was able to bind specifically to DNA in the presence of the r etinoid X receptor (RXR), and transient transfection assays showed tha t the guinea-pig PPAR alpha was capable of being transcriptionally act ivated in a concentration-dependent fashion by the PPs Wy-14,643 and n afenopin. Also, in guinea-pig primary hepatocyte cultures, a dominant negative repressor of PPAR alpha ablated the suppression of spontaneou s apoptosis by PPs. Taken together, these data show that the 'non-resp onsive' guinea-pig expresses active PPAR alpha in the liver at reduced levels, and may be a useful model for exploring the mechanisms underl ying the human response to PPs.