Comparative gene expression profiles induced by PPARγ and PPARα/γ agonists in rat hepatocytes

Species-differential toxic effects have been described with PPAR alpha and PPAR gamma agonists between rodent and human liver. PPAR alpha agonists (fibrates) are potent hypocholesterolemic agents in humans while they induce peroxisome proliferation and tumors in rodent liver. By contrast, PPAR gamma agonists (glitazones) and even dual PPAR alpha/gamma agonists (glitazars) have caused idiosyncratic hepatic and nonhepatic toxicities in human without evidence of any damage in rodent during preclinical studies. The mechanisms involved in such differences remain largely unknown. Several studies have identified the major target genes of PPAR alpha agonists in rodent liver while no comprehensive analysis has been performed on gene expression changes induced by PPAR alpha and dual PPAR alpha/gamma agonists. Here, we investigated transcriptomes of rat hepatocytes after 24 h treatment with two PPAR gamma (troglitazone and rosiglitazone) and two PPAR alpha/gamma (muraglitazar and tesaglitazar) agonists. Although, hierarchical clustering revealed a gene expression profile characteristic of each PPAR agonist class, only a limited number of genes was specifically deregulated by glitazars. Functional analyses showed that many genes known as PPAR alpha targets were also modulated by both PPAR gamma and PPAR alpha/gamma agonists and quantitative differences in gene expression profiles were observed between these two classes. Moreover, most major genes modulated in rat hepatocytes were also found to be deregulated in rat liver after tesaglitazar treatment. Taken altogether, these results support the conclusion that differential toxic effects of PPAR alpha and PPAR gamma agonists in rodent liver do not result from transcriptional deregulation of major PPAR target genes but rather from qualitative and/or quantitative differential responses of a small subset of genes. (C) 2011 Elsevier Inc. All rights reserved.