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This article is part of the supplement: Third Annual MCBIOS Conference. Bioinformatics: A Calculated Discovery

Open Access Proceedings

Differential gene expression in mouse primary hepatocytes exposed to the peroxisome proliferator-activated receptor α agonists

Lei Guo1*, Hong Fang2, Jim Collins3, Xiao-hui Fan1, Stacey Dial1, Alex Wong3, Kshama Mehta3, Ernice Blann1, Leming Shi1, Weida Tong1 and Yvonne P Dragan1

Author Affiliations

1 Division of Systems Toxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA

2 Z-Tech Corporation, 3900 NCTR Road, Jefferson, AR 72079, USA

3 Agilent Technologies, Inc., Santa Clara, CA 95051, USA

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BMC Bioinformatics 2006, 7(Suppl 2):S18  doi:10.1186/1471-2105-7-S2-S18

Published: 26 September 2006

Abstract

Background

Fibrates are a unique hypolipidemic drugs that lower plasma triglyceride and cholesterol levels through their action as peroxisome proliferator-activated receptor alpha (PPARα) agonists. The activation of PPARα leads to a cascade of events that result in the pharmacological (hypolipidemic) and adverse (carcinogenic) effects in rodent liver.

Results

To understand the molecular mechanisms responsible for the pleiotropic effects of PPARα agonists, we treated mouse primary hepatocytes with three PPARα agonists (bezafibrate, fenofibrate, and WY-14,643) at multiple concentrations (0, 10, 30, and 100 μM) for 24 hours. When primary hepatocytes were exposed to these agents, transactivation of PPARα was elevated as measured by luciferase assay. Global gene expression profiles in response to PPARα agonists were obtained by microarray analysis. Among differentially expressed genes (DEGs), there were 4, 8, and 21 genes commonly regulated by bezafibrate, fenofibrate, and WY-14,643 treatments across 3 doses, respectively, in a dose-dependent manner. Treatments with 100 μM of bezafibrate, fenofibrate, and WY-14,643 resulted in 151, 149, and 145 genes altered, respectively. Among them, 121 genes were commonly regulated by at least two drugs. Many genes are involved in fatty acid metabolism including oxidative reaction. Some of the gene changes were associated with production of reactive oxygen species, cell proliferation of peroxisomes, and hepatic disorders. In addition, 11 genes related to the development of liver cancer were observed.

Conclusion

Our results suggest that treatment of PPARα agonists results in the production of oxidative stress and increased peroxisome proliferation, thus providing a better understanding of mechanisms underlying PPARα agonist-induced hepatic disorders and hepatocarcinomas.