+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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



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



Journal of Biological Chemistry 276(34): 31521-7



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.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 045787299

Download citation: RISBibTeXText

PMID: 11418601

DOI: 10.1074/jbc.m103306200


Related references

Differential gene regulation in human versus rodent hepatocytes by peroxisome proliferator-activated receptor (PPAR) a. PPARa fails to induce peroxisome proliferation-associated genes in human cells independently of the level of receptor expression. The Journal of Biological Chemistry 276(34): 521-7, 2001

The transcriptional coactivator peroxisome proliferator activated receptor (PPAR)gamma coactivator-1 alpha and the nuclear receptor PPAR alpha control the expression of glycerol kinase and metabolism genes independently of PPAR gamma activation in human white adipocytes. Diabetes 56(10): 2467-2475, 2007

Application of fluorescent differential display and peroxisome proliferator-activated receptor (PPAR) alpha-null mice to analyze PPAR target genes. Methods in Enzymology 357: 214-240, 2002

Molecular modelling of the peroxisome proliferator-activated receptor alpha (PPAR alpha) from human, rat and mouse, based on homology with the human PPAR gamma crystal structure. Toxicology in Vitro 16(3): 275-280, 2002

Increased expression of peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma in human atherosclerosis. Pathology, Research and Practice 206(7): 429-438, 2010

A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats. Diabetes 47(12): 1841-1847, 1998

Suppression of plasma free fatty acids upregulates peroxisome proliferator-activated receptor (PPAR) alpha and delta and PPAR coactivator 1alpha in human skeletal muscle, but not lipid regulatory genes. Journal of Molecular Endocrinology 33(2): 533-544, 2004

A dominant negative human peroxisome proliferator-activated receptor (PPAR){alpha} is a constitutive transcriptional corepressor and inhibits signaling through all PPAR isoforms. Endocrinology 146(4): 1871-1882, 2005

Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta. Journal of Biological Chemistry 277(29): 26089-26097, 2002

Peroxisome proliferator-activated receptor (PPAR)-gamma expression in human vascular smooth muscle cells: inhibition of growth, migration, and c-fos expression by the peroxisome proliferator-activated receptor (PPAR)-gamma activator troglitazone. American Journal of Hypertension 13(1 Pt 1): 74-82, 2000

Expression of peroxisome proliferator-activated receptor alpha (PPAR alpha) in primary cultures of human vascular endothelial cells. Biochemical and Biophysical Research Communications 246(2): 370-374, 1998

Review of the expression of peroxisome proliferator-activated receptors alpha (PPAR alpha), beta (PPAR beta), and gamma (PPAR gamma) in rodent and human development. Reproductive Toxicology 27(3-4): 246-257, 2008

Highly sensitive upregulation of apolipoprotein A-IV by peroxisome proliferator-activated receptor alpha (PPAR alpha) agonist in human hepatoma cells. Biochemical Pharmacology 74(12): 1738-1746, 2007

Maturation of peroxisomes in differentiating human hepatoblastoma cells (HepG2): possible involvement of the peroxisome proliferator-activated receptor alpha (PPAR alpha). Differentiation; Research in Biological Diversity 64(1): 55-66, 1998

Gene expression profiling of potential peroxisome proliferator-activated receptor (PPAR) target genes in human hepatoblastoma cell lines inducibly expressing different PPAR isoforms. Nuclear Receptor 3(): 3-3, 2005