Therapeutic effects and mechanisms of selective TNF-receptor-1 inhibition in non-alcoholic fatty liver disease

选择性TNF-受体-1抑制治疗非酒精性脂肪肝的疗效及机制

• 批准号: 281791968
• 负责人: Professorin Dr. Heike Bantel
• 金额: --
• 依托单位: Klinik für Gastroenterologie, Hepatologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/281791968?language=en
• 关键词: Therapeutic; effects; mechanisms; selective; TNF

Non-alcoholic fatty liver disease (NAFLD) shows an increasing prevalence and is associated with an increased mortality. The therapeutic possibilities are limited and restricted to life style modifications, since specific drugs for NAFLD treatment are not available so far. TNFalpha has been implicated as an important mediator in the pathogenesis and progression of NAFLD. TNF-mediated liver injury mainly occurs via TNFR1 signaling. In the first funding period we could demonstrate in a high-fat-diet (HFD) model, that treatment of mice with a newly developed anti-TNFR1 antibody significantly reduced liver steatosis, apoptotic liver injury and liver fibrosis. TNFR1-inhibition also resulted in a significant reduction of aminotransferase levels and improvement of insulin resistance. We could demonstrate reduced activation of stress-activated protein kinases and improved insulin-signaling. In addition, endoplasmic reticulum (ER) stress-mediated liver injury was reduced. Based on these promising results we will now investigate the therapeutic effects of anti-TNFR1-treatment on ER-stress regulation as well as on autophagy, which protects against ER-stress but is decreased in progressed NAFLD. In this context, we could observe reduced activation of mTOR, a negative regulator of autophagy, in TNFR1-antibody-treated mice. In addition, human liver tissues of different NAFLD activity will be analyzed for the identified regulators of NAFLD progression. We will further investigate whether the combination of the TNFR1-antibody with a small-molecule ER-stress inhibitor enhances the therapeutic efficiency in NAFLD. Since increased ER-stress and mTOR-activation play an important role in the pathogenesis of NASH-associated hepatocellular carcinoma (HCC), we will also investigate whether TNFR1-inhibition can prevent the HCC development in a NASH-HCC mouse model. This project might therefore open up new insights into signaling pathways and their druggability in NAFLD and associated HCC, which might provide a basis for future clinical trials.

非酒精性脂肪性肝病（NAFLD）的患病率越来越高，并与死亡率增加有关。治疗的可能性是有限的，仅限于生活方式的改变，因为迄今为止还没有用于NAFLD治疗的特定药物。TNF α已被认为是NAFLD发病机制和进展中的重要介质。TNF介导的肝损伤主要通过TNFR 1信号传导发生。在第一个资助期内，我们可以在高脂饮食（HFD）模型中证明，用新开发的抗TNFR 1抗体治疗小鼠可显着减少肝脏脂肪变性，凋亡性肝损伤和肝纤维化。TNFR 1抑制还导致转氨酶水平的显著降低和胰岛素抵抗的改善。我们可以证明减少应激激活蛋白激酶的激活和改善胰岛素信号传导。此外，内质网（ER）应激介导的肝损伤减少。基于这些有希望的结果，我们现在将研究抗TNFR 1治疗对ER应激调节以及对自噬的治疗作用，自噬可保护免受ER应激，但在进展的NAFLD中减少。在这种情况下，我们可以观察到TNFR 1抗体处理的小鼠中自噬的负调节因子mTOR的活化减少。此外，将分析具有不同NAFLD活性的人肝组织中确定的NAFLD进展调节剂。我们将进一步研究TNFR 1抗体与小分子ER应激抑制剂的组合是否增强NAFLD的治疗效率。由于ER应激和mTOR激活增加在NASH相关肝细胞癌（HCC）的发病机制中起重要作用，我们还将研究TNFR 1抑制是否可以预防NASH-HCC小鼠模型中HCC的发展。因此，该项目可能会为NAFLD和相关HCC的信号通路及其药物性开辟新的见解，这可能为未来的临床试验提供基础。