Differential gene expression in mouse liver associated with the hepatoprotective effect of clofibrate

Toxicol Appl Pharmacol. 2007 Jul 15;222(2):169-79. doi: 10.1016/j.taap.2007.04.008. Epub 2007 May 3.

Abstract

Pretreatment of mice with the peroxisome proliferator clofibrate (CFB) protects against acetaminophen (APAP)-induced hepatotoxicity. Previous studies have shown that activation of the nuclear peroxisome proliferator activated receptor-alpha (PPARalpha) is required for this effect. The present study utilizes gene expression profile analysis to identify potential pathways contributing to PPARalpha-mediated hepatoprotection. Gene expression profiles were compared between wild type and PPARalpha-null mice pretreated with vehicle or CFB (500 mg/kg, i.p., daily for 10 days) and then challenged with APAP (400 mg/kg, p.o.). Total hepatic RNA was isolated 4 h after APAP treatment and hybridized to Affymetrix Mouse Genome MGU74 v2.0 GeneChips. Gene expression analysis was performed utilizing GeneSpring software. Our analysis identified 53 genes of interest including vanin-1, cell cycle regulators, lipid-metabolizing enzymes, and aldehyde dehydrogenase 2, an acetaminophen binding protein. Vanin-1 could be important for CFB-mediated hepatoprotection because this protein is involved in the synthesis of cysteamine and cystamine. These are potent antioxidants capable of ameliorating APAP toxicity in rodents and humans. HPLC-ESI/MS/MS analysis of liver extracts indicates that enhanced vanin-1 gene expression results in elevated cystamine levels, which could be mechanistically associated with CFB-mediated hepatoprotection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / administration & dosage
  • Acetaminophen / toxicity
  • Acyl-CoA Oxidase / genetics
  • Acyl-CoA Oxidase / metabolism
  • Amidohydrolases
  • Animals
  • Anticholesteremic Agents / pharmacology
  • Anticholesteremic Agents / therapeutic use
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Chemical and Drug Induced Liver Injury
  • Clofibrate / pharmacology*
  • Clofibrate / therapeutic use
  • Cluster Analysis
  • Cystamine / chemistry
  • Cystamine / metabolism
  • Cysteamine / chemistry
  • Cysteamine / metabolism
  • Enoyl-CoA Hydratase / genetics
  • Enoyl-CoA Hydratase / metabolism
  • GPI-Linked Proteins
  • Gene Expression Profiling / methods*
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Liver Diseases / genetics
  • Liver Diseases / prevention & control
  • Malate Dehydrogenase / genetics
  • Malate Dehydrogenase / metabolism
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Oligonucleotide Array Sequence Analysis / methods
  • PPAR alpha / genetics*
  • PPAR alpha / metabolism
  • Pantetheine / chemistry
  • Pantetheine / metabolism
  • Pantothenic Acid / chemistry
  • Pantothenic Acid / metabolism
  • Peroxisome Proliferators / metabolism
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Anticholesteremic Agents
  • Cell Adhesion Molecules
  • GPI-Linked Proteins
  • PPAR alpha
  • Peroxisome Proliferators
  • Pantothenic Acid
  • Acetaminophen
  • Pantetheine
  • Cysteamine
  • Malate Dehydrogenase
  • Acyl-CoA Oxidase
  • Proteasome Endopeptidase Complex
  • Amidohydrolases
  • pantetheinase
  • Enoyl-CoA Hydratase
  • Clofibrate
  • Cystamine