These authors contributed equally to this work.
Yes-associated protein regulates the hepatic response after bile duct ligation†
Article first published online: 8 AUG 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 56, Issue 3, pages 1097–1107, September 2012
How to Cite
Bai, H., Zhang, N., Xu, Y., Chen, Q., Khan, M., Potter, J. J., Nayar, S. K., Cornish, T., Alpini, G., Bronk, S., Pan, D. and Anders, R. A. (2012), Yes-associated protein regulates the hepatic response after bile duct ligation. Hepatology, 56: 1097–1107. doi: 10.1002/hep.25769
Potential conflict of interest: Nothing to report.
- Issue published online: 28 AUG 2012
- Article first published online: 8 AUG 2012
- Manuscript Accepted: 31 MAR 2012
- Manuscript Received: 14 SEP 2011
- Department of Defense. Grant Number: NF093145
- National Institutes of Health. Grant Number: R01DK081417
- Howard Hughes Medical Institute
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)