Modulation of Non-Alcoholic Steatohepatitis by Pattern Recognition Receptors in Mice: The Role of Toll-Like Receptors 2 and 4

Authors

  • Gyongyi Szabo,

    Corresponding author
    1. Liver Center, Division of Gastroenterology (GS, AV, LR, PM), Department of Medicine, University of Massachusetts Medical School.
      Reprint requests: Gyongyi Szabo, MD, PhD, Professor, Director of Hepatology and Liver Center, Department of Medicine, Univ. of Massachusetts Medical School, LRB 215, 364 Plantation Street, Worcester, MA 01605; Fax: (508) 856-4770; E-mail: gyongyi.szabo@umassmed.edu.
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  • Arumugam Velayudham,

    1. Liver Center, Division of Gastroenterology (GS, AV, LR, PM), Department of Medicine, University of Massachusetts Medical School.
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  • Laszlo Romics Jr,

    1. Liver Center, Division of Gastroenterology (GS, AV, LR, PM), Department of Medicine, University of Massachusetts Medical School.
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  • Pranoti Mandrekar

    1. Liver Center, Division of Gastroenterology (GS, AV, LR, PM), Department of Medicine, University of Massachusetts Medical School.
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Reprint requests: Gyongyi Szabo, MD, PhD, Professor, Director of Hepatology and Liver Center, Department of Medicine, Univ. of Massachusetts Medical School, LRB 215, 364 Plantation Street, Worcester, MA 01605; Fax: (508) 856-4770; E-mail: gyongyi.szabo@umassmed.edu.

Abstract

Abstract: Toll-like receptors (TLR) recognize pathogen-derived molecules and induce downstream activation of inflammatory pathways. Fatty liver has been shown to result in increased sensitivity to lipopolysaccharide (LPS), a TLR4 ligand. In this study, we investigated the roles of TLR2 and TLR4 in liver damage and on cytokine induction in a methionine-choline deficient (MCD) diet-induced model of nonalcoholic steatohepatitis. We found that mice with nonalcoholic fatty liver had increased liver injury and inflammatory cytokine induction after challenge with a TLR4 but not with a TLR2 ligand. TLR2 deficient mice were not protected against the development of steatohepatitis after MCD diet feeding. On the contrary, TLR2−/− mice had significantly higher levels of serum ALT and greater TNF-α levels after LPS challenge suggesting increased liver injury. This was associated with reduced production of IL-6, a cytokine with hepatoprotective effects in fatty liver. Increased liver injury in the MCD diet-fed TLR2−/− mice was associated with reduced baseline and LPS-induced NF-kB and PPRE binding compared to MCS controls. These results demonstrate that TLR2 deficiency results in increased liver injury in association with nonalcoholic steatohepatitis and may suggest a protective role for TLR2-mediated signals in liver injury.

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