Differential gene expression in mouse liver associated with the hepatoprotective effect of clofibrate.
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.
Moffit
Jeffrey S
JS
University of Connecticut, Department of Pharmaceutical Sciences, Storrs, CT 06269, USA.
Koza-Taylor
Petra H
PH
Holland
Ricky D
RD
Thibodeau
Michael S
MS
Beger
Richard D
RD
Lawton
Michael P
MP
Manautou
José E
JE
D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity; D042962:Acyl-CoA Oxidase / Q000235:genetics / Q000378:metabolism; D000581:Amidohydrolases; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D002994:Clofibrate / Q000494:pharmacology* / Q000627:therapeutic use; D016000:Cluster Analysis; D003538:Cystamine / Q000737:chemistry / Q000378:metabolism; D003543:Cysteamine / Q000737:chemistry / Q000378:metabolism; D004746:Enoyl-CoA Hydratase / Q000235:genetics / Q000378:metabolism; D058851:GPI-Linked Proteins; D020869:Gene Expression Profiling / Q000379:methods*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000517:prevention & control; D008291:Malate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D010204:Pantetheine / Q000737:chemistry / Q000378:metabolism; D010205:Pantothenic Acid / Q000737:chemistry / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000924:Anticholesteremic Agents; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D010205:Pantothenic Acid; D000082:Acetaminophen; D010204:Pantetheine; D003543:Cysteamine; D008291:Malate Dehydrogenase; D042962:Acyl-CoA Oxidase; D046988:Proteasome Endopeptidase Complex; D000581:Amidohydrolases; C022314:pantetheinase; D004746:Enoyl-CoA Hydratase; D002994:Clofibrate; D003538:Cystamine