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

• Published in: Toxicology and applied pharmacology 2007-07, Vol.222 (2), p.169-179
• Main Authors: Moffit, Jeffrey S., Koza-Taylor, Petra H., Holland, Ricky D., Thibodeau, Michael S., Beger, Richard D., Lawton, Michael P., Manautou, José E.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Acetaminophen; Acetaminophen - administration & dosage; Acetaminophen - toxicity; Acyl-CoA Oxidase - genetics; Acyl-CoA Oxidase - metabolism; ALDEHYDES; Amidohydrolases; Animals; Anticholesteremic Agents - pharmacology; Anticholesteremic Agents - therapeutic use; ANTIOXIDANTS; Biological and medical sciences; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; CELL CYCLE; Chemical and Drug Induced Liver Injury; Clofibrate; Clofibrate - pharmacology; Clofibrate - therapeutic use; Cluster Analysis; COMPUTER CODES; CYSTAMINE; Cystamine - chemistry; Cystamine - metabolism; CYSTEAMINE; Cysteamine - chemistry; Cysteamine - metabolism; Enoyl-CoA Hydratase - genetics; Enoyl-CoA Hydratase - metabolism; ENZYMES; Gene Expression Profiling - methods; GENES; GPI-Linked Proteins; Hepatoprotection; HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY; LIPIDS; LIVER; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Diseases - genetics; Liver Diseases - prevention & control; Malate Dehydrogenase - genetics; Malate Dehydrogenase - metabolism; Male; Medical sciences; MICE; Mice, Inbred Strains; Mice, Knockout; Oligonucleotide Array Sequence Analysis - methods; Pantetheine; Pantetheine - chemistry; Pantetheine - metabolism; PANTOTHENIC ACID; Pantothenic Acid - chemistry; Pantothenic Acid - metabolism; Peroxisome proliferators; Peroxisome Proliferators - metabolism; PPAR alpha - genetics; PPAR alpha - metabolism; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; RECEPTORS; Reverse Transcriptase Polymerase Chain Reaction; RNA; TOXICITY; Toxicology; Vanin-1
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2007.04.008

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 (PPARα) is required for this effect. The present study utilizes gene expression profile analysis to identify potential pathways contributing to PPARα-mediated hepatoprotection. Gene expression profiles were compared between wild type and PPARα-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.