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

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.

SUBMITTER: Moffit JS

PROVIDER: S-EPMC1989769 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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

Moffit Jeffrey S JS 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

Toxicology and applied pharmacology 20070503 2

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-nul ...[more]

PMID: 17585979

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

Publications

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

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