Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis

Nonalcoholic steatohepatitis (NASH) is a leading cause of liver disease worldwide. However, the molecular basis of how benign steatosis progresses to NASH is incompletely understood, which has limited the identification of therapeutic targets. Here we show that the transcription regulator TAZ (WWTR1) is markedly higher in hepatocytes in human and murine NASH liver than in normal or steatotic liver. Most importantly, silencing of hepatocyte TAZ in murine models of NASH prevented or reversed hepatic inflammation, hepatocyte death, and fibrosis, but not steatosis. Moreover, hepatocyte-targeted expression of TAZ in a model of steatosis promoted NASH features, including fibrosis. In vitro and in vivo mechanistic studies revealed that a key mechanism linking hepatocyte TAZ to NASH fibrosis is TAZ/TEA domain (TEAD)-mediated induction of Indian hedgehog (Ihh), a secretory factor that activates fibrogenic genes in hepatic stellate cells. In summary, TAZ represents a previously unrecognized factor that contributes to the critical process of steatosis-to-NASH progression. [Display omitted] •TAZ/WWTR1 is increased in hepatocytes in human and mouse NASH liver•Hepatocyte TAZ silencing in steatosis blocks inflammation, cell death, and fibrosis•Hepatocyte TAZ silencing in NASH reverses inflammation, cell death, and fibrosis•Hepatocyte TAZ promotes fibrosis by inducing Ihh, a hepatic stellate cell activator Hepatic fibrosis is a key feature of nonalcoholic steatohepatitis (NASH) affecting morbidity. Wang et al. investigate the underlying mechanisms for progression from benign steatosis to NASH and show that the transcription factor TAZ/WWTR1 is increased in mouse and human NASH. Silencing TAZ can prevent or reverse NASH features, notably fibrosis.