Abstract IA23: The role of hepatocyte TAZ in NASH and NASH-HCC

Abstract

Abstract NASH has emerged as the leading cause of chronic liver disease and hepatocellular carcinoma (HCC) worldwide. However, there is a dearth of treatment options, which is due in large part to a poor understanding of NASH pathophysiology, particularly in the conversion of the relatively benign steatosis to clinically important fibrosis and HCC. We hypothesized that the transcription factor TAZ (WWTR1) in hepatocytes (HCs) promotes the progression of steatosis to fibrotic NASH and HCC. We studied liver tissue from humans with NASH and NASH-HCC and used several mouse models, including a dietary model of obesity, insulin resistance, NASH fibrosis, and HCC. NASH mice were treated with various AAV8-H1-shRNAs to silence genes specifically in HCs. The data show that TAZ is markedly increased in HCs in both human and murine NASH liver compared with normal or steatotic liver. In murine models of NASH, silencing of HC TAZ prevents or reverses hepatic inflammation, HC death, and fibrosis. Moreover, HC-targeted expression of TAZ in a mouse model of steatosis promoted NASH features, including fibrosis. Mechanistic studies using cultured cells and molecular-genetic causation studies in mice revealed that a key mechanism linking is TAZ-mediated induction of Indian hedgehog (Ihh), an HC secretory factor that activates fibrogenic genes in hepatic stellate cells (Wang et al., Cell Metabolism). The mechanism of TAZ upregulation in NASH involves a pathway in which excess cholesterol in HCs disrupts the normal proteasomal degradation of TAZ. Prolonged feeding of mice with the NASH diet leads to HCC, with both the tumors and surrounding tissues expressing high levels of TAZ. Silencing TAZ in HCs after advanced NASH has developed eliminates the progression to HCC, and silencing HC TAZ in mice with NASH-HCC shrinks the tumors. The mechanisms of linking TAZ to NASH-HCC likely both niche (surrounding tissue) and oncogenic effects. In conclusion, HC TAZ, whose levels markedly increase during NASH progression via a pathway involving cholesterol enrichment of HCs, plays an essential role in the progression of steatosis to fibrotic NASH and in the progression of NASH to HCC. As such, silencing TAZ in hepatocytes in the setting of early NASH is a potentially powerful new strategy to prevent the progression of NASH to cirrhosis and HCC. Citation Format: Xiaobo Wang, Robert Schwabe, Ira Tabas. The role of hepatocyte TAZ in NASH and NASH-HCC [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr IA23.