Yes-associated protein regulates the hepatic response after bile duct ligation

Abstract

Human chronic cholestatic liver diseases are characterized by cholangiocyte proliferation, hepatocyte injury, and fibrosis. Yes‐associated protein (YAP), the effector of the Hippo tumor‐suppressor pathway, has been shown to play a critical role in promoting cholangiocyte and hepatocyte proliferation and survival during embryonic liver development and hepatocellular carcinogenesis. Therefore, the aim of this study was to examine whether YAP participates in the regenerative response after cholestatic injury. First, we examined human liver tissue from patients with chronic cholestasis. We found more‐active nuclear YAP in the bile ductular reactions of primary sclerosing cholangitis and primary biliary cirrhosis patient liver samples. Next, we used the murine bile duct ligation (BDL) model to induce cholestatic liver injury. We found significant changes in YAP activity after BDL in wild‐type mice. The function of YAP in the hepatic response after BDL was further evaluated with liver‐specific Yap conditional deletion in mice. Ablating Yap in the mouse liver not only compromised bile duct proliferation, but also enhanced hepatocyte necrosis and suppressed hepatocyte proliferation after BDL. Furthermore, primary hepatocytes and cholangiocytes isolated from Yap‐deficient livers showed reduced proliferation in response to epidermal growth factor in vitro. Finally, we demonstrated that YAP likely mediates its biological effects through the modulation of Survivin expression. Conclusion: Our data suggest that YAP promotes cholangiocyte and hepatocyte proliferation and prevents parenchymal damage after cholestatic injury in mice and thus may mediate the response to cholestasis‐induced human liver disease. (HEPATOLOGY 2012;56:1097–1107)

The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease

“…Similar increases in oval cell expansion have also been observed following bile acid-induced injury of the liver, which elevates nuclear YAP levels by enhancing the expression of IQGAP, an inhibitor of cell adhesion (Anakk et al, 2013). Human patients with advanced stage cholestatic liver disease, which results in bile acid-induced ductal injury, display aberrantly high nuclear YAP levels (Bai et al, 2012). Thus, changes in YAP levels appear to be crucial for liver repair and regeneration.…”

“…Thus, changes in YAP levels appear to be crucial for liver repair and regeneration. Indeed, YAP levels are dramatically induced following hepatectomy (Apte et al, 2009), and the deletion of Yap in the mouse liver compromises the regenerative response of hepatocytes (Bai et al, 2012).…”

Crumbs promotes expanded recognition and degradation by the SCF Slimb/β-TrCP ubiquitin ligase

“…Indeed, genetic induction of epithelial wounds in imaginal discs has been shown to up-regulate Yki activity in cells neighboring the wound (74,75). In addition, Yki/ YAP is activated and promotes tissue regeneration upon injury in the vertebrate and fly intestine, as well as in the mouse liver (76)(77)(78)(79)(80)(81).…”

The Biology of YAP/TAZ: Hippo Signaling and Beyond

“…Upon bile duct ligation (a model of cholestatic injury), YAP liver knockout mice display decreased duct cell proliferation and enhanced parenchymal damage, suggesting a positive role for YAP in liver regeneration (10). The phenotypes associated with combined deletion of YAP and TAZ for liver development, homeostasis, and regeneration are unknown.…”