Protein profiling of mouse livers with peroxisome proliferator-activated receptor alpha activation.
Peroxisome proliferator-activated receptor alpha (PPARalpha) 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 PPARalpha 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 PPARalpha 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 approximately 18-fold decrease in expression and a modest approximately 6-fold increase in expression, respectively. In addition, glycine N-methyltransferase, pyrophosphate phosphohydrolase, and protein phosphatase 1D were down-regulated with PPARalpha activation. These observations establish proteomic profiles reflecting a common and predictable pattern of differential protein expression in livers with PPARalpha activation. We conclude that livers with PPARalpha activation are transcriptionally geared towards fatty acid combustion.
Chu
Ruiyin
R
Department of Functional Genomics, Aventis Pharmaceuticals, Inc., Bridgewater, New Jersey 08807, USA. ruiyin.chu@aventis.com
Lim
Hanjo
H
Brumfield
Laura
L
Liu
Hong
H
Herring
Chris
C
Ulintz
Peter
P
Reddy
Janardan K
JK
Davison
Matthew
M
D042962:Acyl-CoA Oxidase / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods; D005227:Fatty Acids / Q000378:metabolism; D020869:Gene Expression Profiling; D008099:Liver / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D020543:Proteome / Q000032:analysis*; D011743:Pyrimidines / Q000008:administration & dosage; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism
D000596:Amino Acids; D005227:Fatty Acids; D011506:Proteins; D020543:Proteome; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D015262:Xenobiotics; C006253:pirinixic acid; D042962:Acyl-CoA Oxidase