Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators

Abstract

We have isolated a human peroxisomal proliferator activated receptor (hPPAR) from a human liver cDNA library. Based on sequence analysis, we have determined that this cDNA encodes the human PPARα. When assayed in a reconstituted hPPAR responsive transcription system in mammalian CV-1 cells, this receptor was shown to be transcriptionally activated by hypolipidemic agents like clofibric acid, and ETYA (5,8,11,14-eicosatetraynoic acid; a synthetic arachidonic acid homolog). When analyzed in CV-1 cells, the rat PPARα was similarly transcriptionally regulated. However, when assayed in a human liver cell line (HepG2) we noticed that ETYA was a more efficient activator of hPPARα than rPPARα. Thus, factors other than the receptor are important in determining the cellular responsiveness to this class of compounds. Interestingly, WY-14,643, another peroxisome proliferator, was a much more potent activator of rPPARα than human PPARα when assayed in both cell lines. This may explain in part why certain fibrates are potent hepatocarcinogens in rodents. Northern analysis indicates that hPPARα and rPPARα are well expressed in heart, kidney and liver. We further demonstrate that hPPARα and human retinoid X receptorα synergistically interact to bind and transactive through a peroxisomal proliferator response element. Thus in a similar cell and promoter context the rat and human PPARs show a differential response to certain activators. Cumulatively these data suggest that differential ligand responsiveness does not provide a complete explanation for the different biological effects exhibited by hypolipidemic drugs when administered to humans and rats.