Comprehensive Analysis of PPAR [Formula: see text]-Dependent Regulation of Hepatic Lipid Metabolism by Expression Profiling

PPAR [Formula: see text] is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPAR [Formula: see text] in hepatic lipid metabolism, many PPAR [Formula: see text]-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPAR [Formula: see text]-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPAR [Formula: see text] target genes, livers from several animal studies in which PPAR [Formula: see text] was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPAR [Formula: see text]-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPAR [Formula: see text]-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein [Formula: see text] polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (HSL, Lipe), and monoglyceride lipase (Mgll). Using an in silico screening approach, one or more PPAR response elements (PPREs) were identified in each of these genes. Regulation of Pnpla2, Lipe, and Mgll, which are involved in triglyceride hydrolysis, was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPAR [Formula: see text] agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPAR [Formula: see text]. Our study illustrates the power of transcriptional profiling to uncover novel PPAR [Formula: see text]-regulated genes and pathways in liver.