Abstract
We compared the ability of rat and human hepatocytes to respond to fenofibric acid and a novel potent phenylacetic acid peroxisome proliferator-activated receptor (PPAR) alpha agonist (compound 1). Fatty acyl-CoA oxidase (FACO) activity and mRNA were increased after treatment with either fenofibric acid or compound 1 in rat hepatocytes. In addition, apolipoprotein CIII mRNA was decreased by both fenofibric acid and compound 1 in rat hepatocytes. Both agonists decreased apolipoprotein CIII mRNA in human hepatocytes; however, very little change in FACO activity or mRNA was observed. Furthermore, other peroxisome proliferation (PP)-associated genes including peroxisomal 3-oxoacyl-CoA thiolase (THIO), peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (HD), peroxisomal membrane protein-70 (PMP-70) were not regulated by PPAR alpha agonists in human hepatocytes. Moreover, other genes that are regulated by PPAR alpha ligands in human hepatocytes such as mitochondrial HMG-CoA synthase and carnitine palmitoyl transferase-1 (CPT-1) were also regulated in HepG2 cells by PPAR alpha agonists. Several stably transfected HepG2 cell lines were established that overexpressed human PPAR alpha to levels between 6- and 26-fold over normal human hepatocytes. These PPAR alpha-overexpressing cells had higher basal mRNA levels of mitochondrial HMG-CoA synthase and CPT-1; however, basal FACO mRNA levels and other PP-associated genes including THIO, HD, or PMP-70 mRNA were not substantially affected. In addition, FACO, THIO, HD, and PMP-70 mRNA levels did not increase in response to PPAR alpha agonist treatment in the PPAR alpha-overexpressing cells, although mitochondrial HMG-CoA synthase and CPT-1 mRNAs were both induced. These results suggest that other factors besides PPAR alpha levels determine the species-specific response of human and rat hepatocytes to the induction of PP.
Highlights
We compared the ability of rat and human hepatocytes to respond to fenofibric acid and a novel potent phenylacetic acid peroxisome proliferator-activated receptor (PPAR) ␣ agonist
Fenofibric acid produced a dose-dependent suppression of apo CIII mRNA levels in both rat and human at the doses that corresponded to those that induced Fatty acyl-CoA oxidase (FACO) activity in rat hepatocytes
A very modest effect of compound 1 was observed in human hepatocytes on FACO activity (ϳ2-fold) at doses up to 10 M; apo CIII mRNA was suppressed at doses as low as 10 nM
Summary
PPAR␣, peroxisome proliferator-activated receptor ␣; apo CIII, apolipoprotein CIII; PPRE, peroxisome proliferator response element; hPPAR␣, human PPAR␣; CHAPS, 3-((3cholamidopropyl)dimethylammonio)-1-propanesulfonic acid; GST, glutathione S-transferase; LBD, ligand binding domain; CBP, CREBbinding protein; PCR, polymerase chain reaction; RT, reverse transcriptase; FACO, fatty acyl-CoA oxidase; CPT-1, carnitine palmitoyl transferase-1; THIO, peroxisomal 3-oxoacyl-CoA thiolase; HD, peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase; CYP4A, cytochrome P450 4A; PMP-70, peroxisomal membrane protein; mtHMGS, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase. Human PPAR␣ overexpression and determined the effect of overexpression on basal and ligand-stimulated expression of several genes known to be responsive in both rat and human hepatocytes as well as peroxisome proliferation-associated genes that are only responsive in rat hepatocytes
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