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

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，而且仅限于生活方式的改变，因为目前还没有治疗NAFLD的特异性药物。TNFalpha在NAFLD的发病和进展中起着重要的中介作用。tnf介导的肝损伤主要通过TNFR1信号通路发生。在第一个资助期，我们可以在高脂肪饮食（HFD）模型中证明，用新开发的抗tnfr1抗体治疗小鼠可显著减少肝脏脂肪变性、细胞凋亡性肝损伤和肝纤维化。tnfr1抑制也导致转氨酶水平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。此外，内质网应激介导的肝损伤减轻。基于这些有希望的结果，我们现在将研究抗tnfr1治疗对内质网应激调节和自噬的治疗作用，自噬可以保护内质网应激，但在进展性NAFLD中会减少。在这种情况下，我们可以观察到，在tnfr1抗体治疗的小鼠中，自噬的负调节因子mTOR的激活降低。此外，将分析不同NAFLD活性的人类肝脏组织，以确定NAFLD进展的调节因子。我们将进一步研究tnfr1抗体与小分子er应激抑制剂联合是否能提高NAFLD的治疗效率。由于内质网应激增加和mtor激活在nash相关肝细胞癌（HCC）的发病机制中起重要作用，我们还将在NASH-HCC小鼠模型中研究tnfr1抑制是否可以阻止HCC的发展。因此，该项目可能为NAFLD和相关HCC的信号通路及其可药物性开辟新的见解，这可能为未来的临床试验提供基础。

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.