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)
Highlights
Human chronic cholestatic liver diseases are characterized by cholangiocyte proliferation, hepatocyte injury, and fibrosis
Liver sections from control patients without chronic cholestatic liver disease and patients with advanced stage (3-4) primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC) were examined for Yes-associated protein (YAP) protein expression
We looked in more detail at the interlobular bile ducts and found strong YAP staining on the plasma membrane of biliary epithelial cell (BEC), but little YAP staining in the nucleus, as revealed by colocalization with BEC membranous marker CK7
Summary
Human chronic cholestatic liver diseases are characterized by cholangiocyte proliferation, hepatocyte injury, and fibrosis. Conclusion: Our data suggest that YAP promotes cholangiocyte and hepatocyte proliferation and prevents parenchymal damage after cholestatic injury in mice and may mediate the response to cholestasis-induced human liver disease. Primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and biliary atresia are examples of cholestatic human liver diseases, as reviewed elsewhere.[1,2] Cholestasis results in bile duct injury caused by the accumulation of toxic hydrophobic bile acids, which damages the periportal hepatocytes.[3] In response to injury, both biliary epithelial cells (BECs) and hepatocytes will proliferate to compensate for their respective loss. The activity of YAP is regulated through the phosphorylation of a conserved serine residue (S112 in mice and S127 in humans) located within the 14-3-3 binding motif, HxRxxS.[13]
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