Differential gene regulation in human versus rodent hepatocytes by peroxisome proliferator-activated receptor (PPAR) alpha - PPAR alpha fails to induce peroxisome proliferation-associated genes in human cells independently of the level of receptor expression

We compared the ability of rat and human hepatocytes to respond to fenofibr ic acid and a novel potent phenylacetic acid peroxisome proliferator-activa ted receptor (PPAR) a agonist (compound 1). Fatty acyl-CoA oxidase (FACO) a ctivity and mRNA were increased after treatment with either fenofibric acid or compound I in rat hepatocytes. In addition, apolipoprotein CIII mRNA wa s decreased by both fenofibric acid and compound I in rat hepatocytes. Both agonists decreased apolipoprotein CIII mRNA in human hepatocytes; however, very little change in FACO activity or mRNA was observed. Furthermore, oth er peroxisome proliferation (PP)-associated genes including peroxisomal 3-o xoacyl-CoA thiolase (THIO), peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-C oA dehydrogenase (HD), peroxisomal membrane protein-70 (PMP-70) were not re gulated by PPAR alpha agonists in human hepatocytes. Moreover, other genes that are regulated by PPAR alpha ligands in human hepatocytes such as mitoc hondrial HMG-CoA synthase and carnitine palmitoyl transferase-1 (CPT-1) wer e also regulated in HepG2 cells by PPAR alpha agonists. Several stably tran sfected HepG2 cell lines were established that overexpressed human PPAR alp ha to levels between 6- and 26-fold over normal human hepatocytes. These PP AR alpha -overexpressing cells had higher basal mRNA levels of mitochondria l EIMG-CoA synthase and CPT-1; however, basal FACO mRNA levels and other PP -associated genes including THIO, HD, or PMP-70 m-RNA were not substantiall y affected. In addition, FACO, THIO, HD, and PMP-70 mRNA levels did not inc rease in response to PPAR alpha agonist treatment in the PPAR alpha -overex pressing cells, although mitochondrial HMG-CoA synthase and CPT-1 mRNAs wer e both induced. These results suggest that other factors besides PPAR alpha levels determine the species-specific response of human and rat hepatocyte s to the induction of PP.