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Molecular and Cellular Biology, July 2004, p. 6288-6297, Vol. 24, No. 14
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.14.6288-6297.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Protein Profiling of Mouse Livers with Peroxisome Proliferator-Activated Receptor Activation

Departments of Functional Genomics,¹ Immunology Platform,² Lead Generation Informatics, Aventis Pharmaceuticals, Inc., Bridgewater, New Jersey 08807,³ Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611⁴

Received 26 February 2004/ Returned for modification 8 April 2004/ Accepted 21 April 2004

Peroxisome proliferator-activated receptor (PPAR) is important in the induction of cell-specific pleiotropic responses, including the development of liver tumors, when it is chronically activated by structurally diverse synthetic ligands such as Wy-14,643 or by unmetabolized endogenous ligands resulting from the disruption of the gene encoding acyl coenzyme A (CoA) oxidase (AOX). Alterations in gene expression patterns in livers with PPAR activation were delineated by using a proteomic approach to analyze liver proteins of Wy-14,643-treated and AOX^–/– mice. We identified 46 differentially expressed proteins in mouse livers with PPAR activation. Up-regulated proteins, including acetyl-CoA acetyltransferase, farnesyl pyrophosphate synthase, and carnitine O-octanoyltransferase, are involved in fatty acid metabolism, whereas down-regulated proteins, including ketohexokinase, formiminotransferase-cyclodeaminase, fructose-bisphosphatase aldolase B, sarcosine dehydrogenase, and cysteine sulfinic acid decarboxylase, are involved in carbohydrate and amino acid metabolism. Among stress response and xenobiotic metabolism proteins, selenium-binding protein 2 and catalase showed a dramatic 18-fold decrease in expression and a modest 6-fold increase in expression, respectively. In addition, glycine N-methyltransferase, pyrophosphate phosphohydrolase, and protein phosphatase 1D were down-regulated with PPAR activation. These observations establish proteomic profiles reflecting a common and predictable pattern of differential protein expression in livers with PPAR activation. We conclude that livers with PPAR activation are transcriptionally geared towards fatty acid combustion.

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