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

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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.