comparative gene expression profiles induced by pparγ and pparαγ agonists in human hepatocytes比较基因表达谱pparγ和pparαγ人类肝细胞受体激动剂.pdfVIP

Comparative Gene Expression Profiles Induced by PPARc and PPARa/c Agonists in Human Hepatocytes 1,2,3 1,2 ´ 1,2 1,2 3 Alexandra Rogue , Carine Lambert , Rozenn Josse , Sebastien Antherieu , Catherine Spire *, 4 ´ 1,2 Nancy Claude , Andre Guillouzo * ´ ´ 1 UMR INSERM U991, Faculte des Sciences Pharmaceutiques et Biologiques, Rennes, France, 2 Universite de Rennes 1, Rennes, France, 3 Biologie Servier, Gidy, France, 4 Institut de Recherches Servier, Courbevoie, France Abstract Background: Several glitazones (PPARc agonists) and glitazars (dual PPARa/c 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 Findings: Primary human hepatocytes and the well-differentiated human hepatoma HepaRG cells were exposed to different concentrations of two PPARc (troglitazone and rosiglitazone) and two PPARa/c (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 AnalysisH revealed large inter-individual variability in the response of the hu