Comparative Gene Expression Profiles Induced by PPARγ and PPARα-γ Agonists in Human HepatocytesReportar como inadecuado




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Background

Several 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 Findings

Primary 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-Significance

This 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.



Autor: Alexandra Rogue, Carine Lambert, Rozenn Jossé, Sebastien Antherieu, Catherine Spire , Nancy Claude, André Guillouzo

Fuente: http://plos.srce.hr/



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