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 expresson.
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.
Lawrence
J W
JW
Department of Safety Assessment, Merck Research Laboratories, Merck and Co., Inc., West Point, Pennsylvania 19486, USA. jeff_lawrence@merck.com
Li
Y
Y
Chen
S
S
DeLuca
J G
JG
Berger
J P
JP
Umbenhauer
D R
DR
Moller
D E
DE
Zhou
G
G
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics; D018528:ATP-Binding Cassette Transporters; D000102:Acetyl-CoA C-Acyltransferase / Q000235:genetics; D000818:Animals; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000235:genetics*; D001483:Base Sequence; D017931:DNA Primers; D004746:Enoyl-CoA Hydratase / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D007535:Isomerases / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D009097:Multienzyme Complexes / Q000235:genetics; D063994:Peroxisomal Bifunctional Enzyme; D020675:Peroxisomes / Q000201:enzymology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000502:physiology*
C063305:ABCD3 protein, human; D018528:ATP-Binding Cassette Transporters; C489272:Abcd3 protein, rat; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D017931:DNA Primers; D008565:Membrane Proteins; D009097:Multienzyme Complexes; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D015094:3-Hydroxyacyl CoA Dehydrogenases; D000102:Acetyl-CoA C-Acyltransferase; C576253:EHHADH protein, human; D004746:Enoyl-CoA Hydratase; D063994:Peroxisomal Bifunctional Enzyme; D007535:Isomerases