BackgroundInnate immune dysfunction contributes to the development and progression of nonalcoholic fatty liver disease (NAFLD), however, its pathogenesis is still incompletely understood. Identifying the key innate immune component responsible for the pathogenesis of NAFLD and clarifying the underlying mechanisms may provide therapeutic targets for NAFLD. Recently, F-box- and WD repeat domain-containing 7 (FBXW7) exhibits a regulatory role in hepatic glucose and lipid metabolism. This study aims to investigate whether FBXW7 controls high-mobility group box 1 protein (HMGB1)-mediated innate immune signaling to improve NAFLD and the mechanism underlying this action.MethodsMice were fed a high-fat diet (HFD) for 12 or 20 weeks to establish NAFLD model. Hepatic overexpression or knockdown of FBXW7 was induced by tail-vein injection of recombinant adenovirus. Some Ad-FBXW7-injected mice fed a HFD were injected intraperitoneally with recombinant mouse HMGB1 to confirm the protective role of FBXW7 in NAFLD via inhibition of HMGB1.ResultsFBXW7 improves NAFLD and related metabolic parameters without remarkable influence of body weight and food intake. Moreover, FBXW7 markedly ameliorated hepatic inflammation and insulin resistance in the HFD-fed mice. Furthermore, FBXW7 dramatically attenuated the expression and release of HMGB1 in the livers of HFD-fed mice, which is associated with inhibition of protein kinase R (PKR) signaling. Thereby, FBXW7 restrains Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) signaling in HFD-fed mouse livers. In addition, exogenous HMGB1 treatment abolished FBXW7-mediated inhibition of hepatic inflammation and insulin resistance in HFD-fed mouse livers.ConclusionsOur results demonstrate a protective role of FBXW7 in NAFLD by abating HMGB1-mediated innate immune signaling to suppress inflammation and consequent insulin resistance, suggesting that FBXW7 is a potential target for therapeutic intervention in NAFLD development.

中文翻译：

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FBXW7 抑制 HMGB1 介导的先天免疫信号以减轻非酒精性脂肪性肝病小鼠模型的肝脏炎症和胰岛素抵抗

背景先天免疫功能障碍有助于非酒精性脂肪性肝病（NAFLD）的发生发展，但其发病机制尚不完全清楚。确定导致 NAFLD 发病机制的关键先天免疫成分并阐明其潜在机制可能为 NAFLD 提供治疗靶点。最近，含有 F-box 和 WD 重复结构域的 7 (FBXW7) 在肝脏葡萄糖和脂质代谢中具有调节作用。本研究旨在研究 FBXW7 是否控制高迁移率族框 1 蛋白 (HMGB1) 介导的先天免疫信号以改善 NAFLD 以及该作用的潜在机制。方法小鼠被喂食高脂饮食 (HFD) 12 或 20 周以改善 NAFLD。建立NAFLD模型。FBXW7 的肝过表达或敲低是通过尾静脉注射重组腺病毒诱导的。一些喂食 HFD 的 Ad-FBXW7 注射小鼠腹膜内注射重组小鼠 HMGB1，以确认 FBXW7 通过抑制 HMGB1 在 NAFLD 中的保护作用。结果 FBXW7 改善 NAFLD 和相关代谢参数，而对体重和食物摄入没有显着影响。此外，FBXW7 显着改善了 HFD 喂养小鼠的肝脏炎症和胰岛素抵抗。此外，FBXW7 显着减弱了 HFD 喂养小鼠肝脏中 HMGB1 的表达和释放，这与抑制蛋白激酶 R (PKR) 信号传导有关。因此，FBXW7 抑制了 HFD 喂养的小鼠肝脏中的 Toll 样受体 4 (TLR4) 和晚期糖基化终产物 (RAGE) 信号传导的受体。此外，