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

Abstract

Peroxisome proliferator-activated receptor α (PPARα) 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 PPARα 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 PPARα 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 PPARα activation. These observations establish proteomic profiles reflecting a common and predictable pattern of differential protein expression in livers with PPARα activation. We conclude that livers with PPARα activation are transcriptionally geared towards fatty acid combustion.