Peroxisome proliferation is a well-defined pleiotropic effect that is mediated by the ligand inducible transcription factor peroxisome proliferator-activated receptor (PPAR) alpha. Because marked peroxisome proliferation occurs in rodents but not in humans, we aimed to elucidate the molecular and cellular determinants of this species-specificity in hepatocytes. Analysis of peroxisomal marker enzyme activities confirmed that peroxisome proliferators induced acyl-CoA oxidase (ACOX) and to a lesser extent catalase in rat hepatocytes, but not in human hepatoma HepG2 cells. Transient transfection assays revealed that ciprofibrate and Wy 14,643 induced rat but not human PPARalpha-mediated reporter gene activity in rat FAO and primary hepatocytes on rat but not on human PPARalpha response elements (PPREs). In contrast, in human HepG2 and primary human hepatocytes, peroxisome proliferators did not induce either human or rat PPARalpha activity regardless of rat or human PPRE sequences. In addition, no induction of ACOX gene expression was observed in human hepatocytes independent of the expression level of human PPARalpha. Remarkably, no distinct peroxisome proliferation related responses were observed in human hepatocytes when rat PPARalpha was transfected, although human hepatocytes were responsive to PPARalpha-mediated induction of carnitine palmitoyl transferase-1A and 3-hydroxy-3-methylglutaryl-CoA synthase. These results confirmed that PPARalpha and PPREs are important determinants for the species-specificity of peroxisome proliferation. Nevertheless, our results showed that human hepatocytes limit the extent of peroxisome proliferation regardless of PPARalpha expression.
Clofibric Acid/analogs & derivatives , Hepatocytes/metabolism , Peroxisome Proliferator-Activated Receptors/metabolism , Peroxisome Proliferators/toxicity , Acyl-CoA Oxidase/genetics , Acyl-CoA Oxidase/metabolism , Animals , Carnitine Acyltransferases/metabolism , Catalase/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Clofibrate/toxicity , Clofibric Acid/toxicity , Fibric Acids , Gene Expression Regulation , Hepatocytes/drug effects , Hepatocytes/enzymology , Humans , Male , Peroxisome Proliferator-Activated Receptors/biosynthesis , Peroxisome Proliferator-Activated Receptors/genetics , Promoter Regions, Genetic , Pyrimidines/toxicity , Rats , Rats, Wistar , Response Elements , Species Specificity , Transfection
