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Yes‐associated protein regulates the hepatic response after bile duct ligation
Author(s) -
Bai Haibo,
Zhang Nailing,
Xu Yang,
Chen Qian,
Khan Mehtab,
Potter James J.,
Nayar Suresh K.,
Cornish Toby,
Alpini Gianfranco,
Bronk Steven,
Pan Duojia,
Anders Robert A.
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25769
Subject(s) - cholangiocyte , cholestasis , hepatocyte , primary sclerosing cholangitis , liver injury , medicine , hepatology , cancer research , biology , hepatocyte growth factor , bile duct , liver regeneration , endocrinology , pathology , receptor , microbiology and biotechnology , regeneration (biology) , in vitro , biochemistry , disease
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. (H EPATOLOGY 2012;56:1097–1107)