Fig. 7

Schematic representation of the role of YAP/TAZ in normal and chronic injured liver. In normal liver (A), YAP activation after liver injury induces liver regeneration by promoting the formation of a new bile duct network through direct BEC proliferation or/and hepatocyte dedifferentiation to HPCs which can trans-differentiate to BECs. The creation of a new bile duct network is necessary to prevent cholestasis which impairs liver regeneration by affecting immune cell recruitment and function. Once activated in hepatocytes, YAP/TAZ signaling interacted with other signaling pathways, which mediate the recruitment and induction of KCs releasing mitogenic cytokines for parenchymal and/or non-parenchymal cells. Activated KCs also operate the phagocytosis of cell debris to allow a proper tissue regeneration. In addition, Hedeghog/YAP-mediated activation of HSCs promotes liver regeneration through ECM protein synthesis. In chronic diseased liver (B), where the predetermined threshold for proper liver regeneration is exceeded, YAP activation promotes a wound healing response. Indeed, chronic disease induces a persistent regeneration response in the liver, which is associated to extensive accumulation of ECM and disruption of normal hepatic structure and function. Thus, YAP activation in liver cells results in a reparative process which is characterized by liver fibrosis development, due to (i) Hedgehog/YAP-mediated glutaminolysis activation in quiescent HSCs which promote their differentiation into myofibroblastic HSCs; (ii) YAP-dependent Cyr61 gene induction in hepatocytes which determine the recruitment of macrophages in the injured liver that release inflammatory and pro-fibrogenic cytokines; (iii) Nrf2-dependent YAP activation which is associated to inhibition of NLRP3 inflammasome in macrophages determining their polarization toward the M2 phenotype associated to the release of anti-inflammatory and reparative cytokines