Departments of Cardiology and Clinical Pharmacy, Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin, China.
Hepatology. 2018 Nov;68(5):1769-1785. doi: 10.1002/hep.30066. Epub 2018 Oct 4.
There is no effective treatment method for nonalcoholic fatty liver disease (NAFLD), the most common liver disease. The exact mechanism underlying the pathogenesis of NAFLD remains to be elucidated. Here, we report that tumor necrosis factor receptor-associated ubiquitous scaffolding and signaling protein (TRUSS) acts as a positive regulator of NAFLD and in a variety of metabolic disorders. TRUSS expression was increased in the human liver specimens with NAFLD or nonalcoholic steatohepatitis, and in the livers of high-fat diet (HFD)-induced and genetically obese mice. Conditional knockout of TRUSS in hepatocytes significantly ameliorated hepatic steatosis, insulin resistance, glucose intolerance, and inflammatory responses in mice after HFD challenge or in spontaneous obese mice with normal chow feeding. All of these HFD-induced pathological phenotypes were exacerbated in mice overexpressing TRUSS in hepatocytes. We show that TRUSS physically interacts with the inhibitor of nuclear factor κB α (IκBα) and promotes the ubiquitination and degradation of IκBα, which leads to aberrant activation of nuclear factor κB (NF-κB). Overexpressing IκBα , a phosphorylation-resistant mutant of IκBα, in the hepatocyte-specific TRUSS overexpressing mice almost abolished HFD-induced NAFLD and metabolic disorders. Conclusion: Hepatocyte TRUSS promotes pathological stimuli-induced NAFLD and metabolic disorders, through activation of NF-κB by promoting ubiquitination and degradation of IκBα. Our findings may provide a strategy for the prevention and treatment of NAFLD by targeting TRUSS.
目前，非酒精性脂肪性肝病（NAFLD）——最常见的肝脏疾病——尚无有效的治疗方法。NAFLD 发病机制的确切机制仍有待阐明。在这里，我们报告肿瘤坏死因子受体相关普遍支架和信号蛋白（TRUSS）作为 NAFLD 和各种代谢紊乱的正调节剂。TRUSS 在患有 NAFLD 或非酒精性脂肪性肝炎的人类肝脏标本中以及高脂肪饮食（HFD）诱导和遗传性肥胖小鼠的肝脏中表达增加。在 HFD 挑战后或在正常饮食喂养的自发性肥胖小鼠中，条件性敲除肝细胞中的 TRUSS 可显著改善肝脂肪变性、胰岛素抵抗、葡萄糖不耐受和炎症反应。在肝细胞中过表达 TRUSS 的小鼠中，所有这些 HFD 诱导的病理表型均加剧。我们表明 TRUSS 与核因子κBα（NF-κB）抑制剂（IκBα）物理相互作用，并促进 IκBα 的泛素化和降解，从而导致 NF-κB 的异常激活。在肝细胞特异性 TRUSS 过表达小鼠中过表达 IκBα，一种 IκBα 的磷酸化抗性突变体，几乎消除了 HFD 诱导的 NAFLD 和代谢紊乱。结论：肝细胞 TRUSS 通过促进 IκBα 的泛素化和降解来激活 NF-κB，从而促进病理刺激诱导的 NAFLD 和代谢紊乱。我们的研究结果可能为通过靶向 TRUSS 预防和治疗 NAFLD 提供一种策略。
