Differential liver sensitization to Toll-like receptor pathways in mice with alcoholic fatty liver

Authors

  • Thierry Gustot,

    Corresponding author
    1. Division of Gastroenterology and Hepato-Pancreatology, Erasme Hospital, Brussels, Belgium
    2. Laboratory of Experimental Gastroenterology, Free University of Brussels, Brussels, Belgium
    • Division of Gastroenterology and Hepato-Pancreatology, Erasme University Hospital, Free University of Brussels, 808 Route de Lennik, B 1070 Brussels, Belgium
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    • fax: (32) 2-555-6197

  • Arnaud Lemmers,

    1. Laboratory of Experimental Gastroenterology, Free University of Brussels, Brussels, Belgium
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  • Christophe Moreno,

    1. Division of Gastroenterology and Hepato-Pancreatology, Erasme Hospital, Brussels, Belgium
    2. Laboratory of Experimental Gastroenterology, Free University of Brussels, Brussels, Belgium
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  • Nathalie Nagy,

    1. Division of Pathology, Erasme Hospital, Brussels, Belgium
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  • Eric Quertinmont,

    1. Laboratory of Experimental Gastroenterology, Free University of Brussels, Brussels, Belgium
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  • Charles Nicaise,

    1. Laboratory of Experimental Gastroenterology, Free University of Brussels, Brussels, Belgium
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  • Denis Franchimont,

    1. Division of Gastroenterology and Hepato-Pancreatology, Erasme Hospital, Brussels, Belgium
    2. Laboratory of Experimental Gastroenterology, Free University of Brussels, Brussels, Belgium
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  • Hubert Louis,

    1. Division of Gastroenterology and Hepato-Pancreatology, Erasme Hospital, Brussels, Belgium
    2. Laboratory of Experimental Gastroenterology, Free University of Brussels, Brussels, Belgium
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  • Jacques Devière,

    1. Division of Gastroenterology and Hepato-Pancreatology, Erasme Hospital, Brussels, Belgium
    2. Laboratory of Experimental Gastroenterology, Free University of Brussels, Brussels, Belgium
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  • Olivier Le Moine

    1. Division of Gastroenterology and Hepato-Pancreatology, Erasme Hospital, Brussels, Belgium
    2. Laboratory of Experimental Gastroenterology, Free University of Brussels, Brussels, Belgium
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  • Potential conflict of interest: Nothing to report.

Abstract

Gut-derived, endotoxin-mediated hepatocellular damage has been postulated to play a crucial role in the pathogenesis of alcohol-induced liver injury in rodents. Endotoxins induce production of tumor necrosis factor α (TNF-α) by Kupffer cells via Toll-like receptor (TLR) 4 and contribute to liver injury. This study addressed the contribution of other TLRs and ligands to alcoholic fatty liver. C57Bl6/J mice were fed a modified Lieber-DeCarli diet. Serum aminotransferase measurements, histological analysis, and quantification of liver TNF-α and TLR1-9 messenger RNA (mRNA) were performed. The effect of TLR ligands on liver injury was assessed in vivo. Neomycin and metronidazole or diphenyleneiodonium sulfate (DPI) were administered to evaluate the role of gut bacteria and NADPH oxidase activity, respectively, in hepatic TLR expression. Enteral ethanol (EtOH) exposure induced steatosis and increased liver weight, aminotransferase levels, and expression of TLR1, 2, 4, 6, 7, 8, and 9 liver mRNA. Injection of lipoteichoic acid, peptidoglycan (PGN), lipopolysaccharide (LPS), loxoribine, and oligonucleotide containing CpG (ISS-ODN) increased TNF-α mRNA expression more in the livers of EtOH-fed mice than in control mice. PGN, LPS, flagellin, and ISS-ODN induced liver inflammatory infiltrate in EtOH-fed mice but not control mice. Addition of antibiotics reduced the severity of alcoholic fatty liver without affecting TLR expression, whereas daily DPI injections reduced the EtOH-mediated upregulation of TLR2, 4, 6, and 9 mRNA. In conclusion, EtOH-fed mice exhibited an oxidative stress dependent on upregulation of multiple TLRs in the liver and are sensitive to liver inflammation induced by multiple bacterial products recognized by TLRs. (HEPATOLOGY 2006;43:989–1000.)

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