Nuclear factor high-mobility group box1 mediating the activation of toll-like receptor 4 signaling in hepatocytes in the early stage of nonalcoholic fatty liver disease in mice

Authors

  • Liang Li,

    1. International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
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    • The first three authors contributed equally to this work.

  • Lei Chen,

    1. International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
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    • The first three authors contributed equally to this work.

  • Liang Hu,

    1. International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
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    • The first three authors contributed equally to this work.

  • Yuan Liu,

    1. International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
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  • Han-Yong Sun,

    1. International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
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  • Jing Tang,

    1. International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
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  • Yu-Jie Hou,

    1. International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
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  • Yan-Xin Chang,

    1. International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
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  • Qian-Qian Tu,

    1. International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
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  • Gen-Sheng Feng,

    1. International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
    2. Department of Pathology, School of Medicine, and Section of Molecular Biology, Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA
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  • Feng Shen,

    1. Eastern Hepatobiliary Surgery Hospital, SMMU, Shanghai, China
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  • Meng-Chao Wu,

    1. Eastern Hepatobiliary Surgery Hospital, SMMU, Shanghai, China
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  • Hong-Yang Wang

    Corresponding author
    1. International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
    2. National Laboratory for Oncogenes and Related Genes, Cancer Institute in RuiJing Hospital, Shanghai JiaoTong University, Shanghai, China
    • Academician of Chinese Academy of Engineering, Professor and Director, International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 225 Changhai Road, 200438 Shanghai, China; National Laboratory for Oncogenes and Related Genes, Cancer Institute in RuiJing Hospital, Shanghai Jiao Tong University, 200441, Shanghai, China
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    • fax: 86 21 6556 6851


  • Potential conflict of interest: Nothing to report.

  • Supported by the state Key project for liver cancer (2008ZX10002), National High-Tech Research and Development Program of China (2006AA02A249, 08Z20), National Science Fund for Distinguished Young Scholars (30921006), Key Program of National Natural Science Foundation of China (90713032), and Science Foundation of Shanghai (10QA1408700, 10JC1418500 and 09CG33).

Abstract

One of the challenges surrounding nonalcoholic fatty liver disease (NAFLD) is to discover the mechanisms that underlie the initiation of it. The aim of the present study was to elucidate the effects of Toll-like receptor 4 (TLR4) signaling in liver parenchymal cells during the early stage of NAFLD. Male TLR4-wildtype, TLR4-knockout, TLR2-knockout, MyD88-knockout, and TRIF-knockout mice were fed a normal diet or high-fat diet (HFD). Liver steatosis, alanine aminotransferase levels, nuclear translocation of nuclear factor kappa B (NF-κB) (p65), macrophage accumulation, and neutrophil infiltration were assessed. Using Kupffer cell depletion or bone marrow transplantation, we examined the potential role of Kupffer cells and myeloid infiltrating cells during the initiation of NAFLD. Immunohistochemistry and western blotting were implemented to determine the release of high-mobility group box1 (HMGB1). The neutral-antibody against HMGB1 was used to block the activity of free HMGB1. Here we report that the activation of TLR4 signaling in hepatocytes, accompanied with the relocation of P65 in nucleus, was proven to play an important role during the initiation of NAFLD. Importantly, HMGB1 releasing from hepatocytes in response to free fatty acid (FFA) infusion was first reported as the key molecule for the TLR4/MyD88 activation and cytokines expression in vitro and in vivo. Treatment with neutralizing antibody to HMGB1 protects against FFA-induced tumor necrosis factor alpha and interleukin-6 production. Conclusion: Our study supports the notion that TLR4/MyD88 signaling in liver parenchymal cells plays a pivotal role during the early progression of HFD-induced NAFLD, in which free HMGB1 served as a positive component mediating TLR4 activation. (HEPATOLOGY 2011;)

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