Hippo signalling in the liver: role in development, regeneration and disease

The Hippo signalling pathway has emerged as a major player in many aspects of liver biology, such as development, cell fate determination, homeostatic function and regeneration from injury. The regulation of Hippo signalling is complex, with activation of the pathway by diverse upstream inputs including signals from cellular adhesion, mechanotransduction and crosstalk with other signalling pathways. Pathological activation of the downstream transcriptional co-activators yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ, encoded by WWTR1 ), which are negatively regulated by Hippo signalling, has been implicated in multiple aspects of chronic liver disease, such as the development of liver fibrosis and tumorigenesis. Thus, development of pharmacological inhibitors of YAP–TAZ signalling has been an area of great interest. In this Review, we summarize the diverse roles of Hippo signalling in liver biology and highlight areas where outstanding questions remain to be investigated. Greater understanding of the mechanisms of Hippo signalling in liver function should help facilitate the development of novel therapies for the treatment of liver disease. In this Review, Russell and Camargo summarize the role of the Hippo signalling pathway in liver development, homeostasis, regeneration and disease, and discuss development of potential therapeutics for liver diseases such as fibrosis and cancer. Key points During embryonic liver development, yes-associated protein 1 (YAP) activity in hepatoblasts suppresses hepatocyte differentiation and is essential for proper cholangiocyte maturation and formation of the intrahepatic biliary network. During adult liver homeostasis, YAP activity is largely dispensable in hepatocytes but is required for the maintenance of mature cholangiocytes through its protective effects against exposure to hydrophobic bile acids. YAP is an important regulator of liver cell fate owing to its ability to promote hepatocyte-to-cholangiocyte transdifferentiation, and its activity in cholangiocytes drives the ductular reaction during chronic liver injury. YAP–transcriptional co-activator with PDZ-binding motif (TAZ) activity in hepatocytes, hepatic stellate cells, Kupffer cells and liver sinusoidal endothelial cells promotes inflammation and fibrosis in multiple models of nonalcoholic steatohepatitis and chemical-induced liver fibrosis. YAP is a potent oncogene and high YAP activity is frequently observed in he