Differences in the formation of PPAR alpha-RXR/acoPPRE complexes between responsive and nonresponsive species upon fibrate administration

Peroxisome proliferator-activated receptor-alpha (PPAR alpha) is responsibl e for the hypolipidemic, peroxisome proliferation and carcinogenic effects of fibrates. Rats and mice are responsive, but guinea pigs and primates are resistant to the proliferative and carcinogenic effects of these drugs, bu t the hypolipidemic effect is still manifest. It is not yet clear whether h umans should be considered unresponsive, and there is concern about the lon g-term safety of fibrates. We present molecular evidence for the reported r esistance of human cells to peroxisome proliferation by describing a defici ent interaction of nuclear extracts from human cells with an acyl-CoA oxida se (ACO)-peroxisome proliferator response element probe upon fibrate additi on. Electrophoretic mobility shift assay analysis showed that ciprofibrate elicited a concentration-dependent increase in the binding of nuclear extra cts from cells of rat (Morris) and human (HepG2) origin to an ACO-peroxisom e proliferator response element probe, although in HepG2 cells the increase was of marginal statistical significance. In Morris cells, the increase wa s more marked than in HepG2 cells (4-fold versus 1.5-fold at 0.2 mM ciprofi brate), and maximal binding was achieved earlier in Morris (30 min) than in HepG2 cells (3 h). Morris cells responded to the addition of ciprofibrate by increasing the levels of ACO mRNA, whereas HepG2 did not. The ratio betw een PPAR beta/PPAR alpha mRNAs was higher in HepG2 cells than in Morris cel ls (3.2 versus 1.9), pointing to an antagonizing effect of PPAR beta on PPA R alpha activity. These results were obtained in untransfected cells expres sing their own basal set of receptors. We also provide evidence of the tran slocation of PPAR alpha from the cytosol to the nucleus upon activation by ciprofibrate.