In addition to insulin resistance and type II diabetes, the obesity epidemic had resulted in a large increase in the incidence of non-alcoholic fatty liver disease (NAFLD), which ranges in its manifestations from simple steatosis without liver inflammation and fibrosis to NASH, which is accompanied by liver damage and fibrosis. The mechanisms that govern the progression from simple steatosis to NASH are obscure, but are thought to depend on secondary risk factors that act together with obesity. To study these mechanisms we have developed a new mouse model of NASH which closely mimics all of the features of human NASH. This model is based on the feeding of MUP-uPA mice, which specifically express urokinase plasminogen activator (uPA) in their hepatocytes. Unlike wild type mice, which only develop simple steatosis and insulin resistance after feeding with high fat diet (HFD), MUP-uPA mice on HFD exhibit pronounced liver damage, inflammation, fibrosis and all the classical signs of NASH. The key factors that drive NASH pathogenesis in MUP-uPA mice on HFD are ER stress and excessive TNF production. Interestingly, activation of type I TNF receptor (TNFR1) also controls lipogenesis and steatosis in MUP-uPA mice. Both ER stress and TNFR1 signaling appear to be suitable therapeutic targets for the prevention of NASH and inhibition of its progression to steatotic hepatocellular carcinoma.
Citation Format: Michael Karin. ER stress and TNF signaling control the progression from simple steatosis to non-alcoholic steatohepatitis (NASH). [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr PL03-03.