Comprehensive Analysis of PPAR alpha-Dependent Regulation of Hepatic Lipid Metabolism by Expression Profiling

PPAR alpha 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 alpha in hepatic lipid metabolism, many PPAR alpha-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPAR alpha-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPAR alpha target genes, livers from several animal studies in which PPAR alpha was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPAR alpha-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPAR alpha-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein beta 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 alpha 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 alpha. Our study illustrates the power of transcriptional profiling to uncover novel PPARa-regulated genes and pathways in liver. Copyright (C) 2007 Maryam Rakhshandehroo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.