Abstract
BackgroundSeveral glitazones (PPARγ agonists) and glitazars (dual PPARα/γ agonists) have been developed to treat hyperglycemia and, simultaneously, hyperglycemia and dyslipidemia, respectively. However, most have caused idiosyncratic hepatic or extrahepatic toxicities through mechanisms that remain largely unknown. Since the liver plays a key role in lipid metabolism, we analyzed changes in gene expression profiles induced by these two types of PPAR agonists in human hepatocytes.Methodology/Principal FindingsPrimary human hepatocytes and the well-differentiated human hepatoma HepaRG cells were exposed to different concentrations of two PPARγ (troglitazone and rosiglitazone) and two PPARα/γ (muraglitazar and tesaglitazar) agonists for 24 h and their transcriptomes were analyzed using human pangenomic Agilent microarrays. Principal Component Analysis, hierarchical clustering and Ingenuity Pathway Analysis® revealed large inter-individual variability in the response of the human hepatocyte populations to the different compounds. Many genes involved in lipid, carbohydrate, xenobiotic and cholesterol metabolism, as well as inflammation and immunity, were regulated by both PPARγ and PPARα/γ agonists in at least a number of human hepatocyte populations and/or HepaRG cells. Only a few genes were selectively deregulated by glitazars when compared to glitazones, indicating that PPARγ and PPARα/γ agonists share most of their target genes. Moreover, some target genes thought to be regulated only in mouse or to be expressed in Kupffer cells were also found to be responsive in human hepatocytes and HepaRG cells.Conclusions/SignificanceThis first comprehensive analysis of gene regulation by PPARγ and PPARα/γ agonists favor the conclusion that glitazones and glitazars share most of their target genes and induce large differential changes in gene profiles in human hepatocytes depending on hepatocyte donor, the compound class and/or individual compound, thereby supporting the occurrence of idiosyncratic toxicity in some patients.
Highlights
Peroxisome proliferator-activated receptors (PPARs) are an important class of ligand-activated transcription factors involved in the regulation of nutrient homeostasis, as well as a variety of other biological processes [1]
Synthetic drugs activating PPARa and PPARc are in clinical use: the former typified by fibrates, are used to treat dyslipidemia, while the latter include glitazones that act as insulin sensitizers in type 2 diabetes mellitus [3]
Primary human hepatocytes (PHH) Human hepatocytes from four adult donors undergoing resection for primary and secondary tumors were obtained by collagenase perfusion of histologically normal liver fragments [11] (Table S1)
Summary
Peroxisome proliferator-activated receptors (PPARs) are an important class of ligand-activated transcription factors involved in the regulation of nutrient homeostasis, as well as a variety of other biological processes [1]. Dual PPARa and PPARc agonists have been developed by the pharmaceutical industry for the simultaneous treatment of hyperglycemia and dyslipidemia, but the first developed drugs, muraglitazar (MURA) and tesaglitazar (TESA), were terminated during clinical trials due to cardiac and renal side-effects, despite the absence of noticeable hepatic lesions [5]. The mechanisms of these idiosyncratic toxicities of glitazones and glitazars in humans remain unclear. Since the liver plays a key role in lipid metabolism, we analyzed changes in gene expression profiles induced by these two types of PPAR agonists in human hepatocytes
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