Identification of Novel Peroxisome Proliferator-Activated Receptor (PPAR) Target Genes in Mouse Liver Using cDNA Microarray Analysis

Authors: CHERKAOUI-MALKI M.¹; MEYER K.¹; CAO W-Q.¹; LATRUFFE N.²; YELDANDI A.V.¹; RAO M.S.¹; BRADFIELD C.A.³; REDDY J.K.¹

Source: Gene Expression, Volume 9, Number 6, 2001 , pp. 291-304(14)

Publisher: Cognizant Communication Corporation

Abstract:

Peroxisome proliferators, which function as peroxisome proliferator-activated receptor- (PPAR) agonists, are a group of structurally diverse nongenotoxic hepatocarcinogens including the fibrate class of hypolipidemic drugs that induce peroxisome proliferation in liver parenchymal cells. Sustained activation of PPAR by these agents leads to the development of liver tumors in rats and mice. To understand the molecular mechanisms responsible for the pleiotropic effects of these agents, we have utilized the cDNA microarray to generate a molecular portrait of gene expression in the liver of mice treated for 2 weeks with Wy-14,643, a potent peroxisome proliferator. PPAR activation resulted in the stimulation of expression (fourfold or greater) of 36 genes and decreased the expression (fourfold or more decrease) of 671 genes. Enhanced expression of several genes involved in lipid and glucose metabolism and many other genes associated with peroxisome biogenesis, cell surface function, transcription, cell cycle, and apoptosis has been observed. These include: CYP2B9, CYP2B10, monoglyceride lipase, pyruvate dehydrogenase-kinase-4, cell death-inducing DNA-fragmentation factor-, peroxisomal biogenesis factor 11, as well as several cell recognition surface proteins including annexin A2, CD24, CD39, lymphocyte antigen 6, and retinoic acid early transcript-, among others. Northern blotting of total RNA extracted from the livers of PPAR^-/- mice and from mice lacking both PPAR and peroxisomal fatty acyl-CoA oxidase (AOX), that were fed control and Wy-14,643-containing diets for 2 weeks, as well as time course of induction following a single dose of Wy-14,643, revealed that upregulation of genes identified by microarray procedure is dependent upon peroxisome proliferation vis-à-vis PPAR. However, cell death-inducing DNA-fragmentation factor- mRNA, which is increased in the livers of wild-type mice treated with peroxisome proliferators, was not enhanced in AOX^-/- mice with spontaneous peroxisome proliferation. These observations indicate that the activation of PPAR leads to increased and decreased expression of many genes not associated with peroxisomes, and that delayed onset of enhanced expression of some genes may be the result of metabolic events occurring secondary to PPAR activation and alterations in lipid metabolism.

Keywords: Peroxisome proliferator-activated receptor- (PPAR) Peroxisome proliferator Liver DNA microarray analysis

Language: English

Document Type: Research article

Affiliations: 1: *Department of Pathology, Northwestern University Medical School, Chicago, IL 60611-3008 2: †Laboratoíre de Biologie Moléculaire et Cellulaire, Universite de Bourgogne, BP138, 21004 Dijon, France 3: ‡McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, WI 53706

Publication date: 2001-01-01

• The Molecular and Cellular Biology area of Gene Expression covers all aspects of the gene including it structure, functions, and regulation in prokaryotes, eukaryotes, and viruses; molecular and cell biological aspects of cell growth and development, chromatin structure and function. These include topics such as DNA replication, DNA repair, gene transcription, transcriptional control, RNA processing, posttranscriptional control, oncogenes, molecular mechanisms of action of hormones, molecular mechanism of cellular differentiation, growth and development, protein synthesis, and posttranslational control.
  The Molecular and Cellular Neuroscience area of Gene Expression covers all aspects of gene expression as described but is devoted exclusively to the nervous system in health and disease. Topics include studies of neurogenesis, development, aging, and neurodegeneration. Complex neural systems, motor control, special senses, and higher cortical function, when viewed from the perspective of gene expression, are appropriate for the journal. Research related to molecular mechanisms of drug tolerance, dependence, and withdrawal are solicited. Manuscripts on state-of-the-art methods and protocols for molecular profiling of neuronal structure and function are welcome.

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• By this author: CHERKAOUI-MALKI M. ;  MEYER K. ;  CAO W-Q. ;  LATRUFFE N. ;  YELDANDI A.V. ;  RAO M.S. ;  BRADFIELD C.A. ;  REDDY J.K.

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