Nuclear Factor High-mobility Group Box1 Mediating the Activation of Toll-like Receptor 4 Signaling in Hepatocytes in the Early Stage of Non-alcoholic Fatty Liver Disease in Mice

Journal of Clinical and Experimental Hepatology
L LiLiang Hu

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 this 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 aminotrans-ferase 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 ...Continue Reading

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