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

Haibo Bai, Nailing Zhang, Yang Xu, Qian Chen, Mehtab Khan, James John Potter, Suresh K. Nayar, Toby Cornish, Gianfranco Alpini, Steven Bronk, Duojia Pan, Robert A Anders

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1097-1107
Number of pages11
JournalHepatology
Volume56
Issue number3
DOIs
StatePublished - Sep 2012

Fingerprint

Bile Ducts
Ligation
Hepatocytes
Liver
Proteins
Cholestasis
Wounds and Injuries
Liver Diseases
Sclerosing Cholangitis
Biliary Liver Cirrhosis
Epidermal Growth Factor
Bile
Embryonic Development
Carcinogenesis
Fibrosis
Necrosis
Survival
Neoplasms

ASJC Scopus subject areas

  • Hepatology

Cite this

Yes-associated protein regulates the hepatic response after bile duct ligation. / Bai, Haibo; Zhang, Nailing; Xu, Yang; Chen, Qian; Khan, Mehtab; Potter, James John; Nayar, Suresh K.; Cornish, Toby; Alpini, Gianfranco; Bronk, Steven; Pan, Duojia; Anders, Robert A.

In: Hepatology, Vol. 56, No. 3, 09.2012, p. 1097-1107.

Research output: Contribution to journalArticle

Bai, H, Zhang, N, Xu, Y, Chen, Q, Khan, M, Potter, JJ, Nayar, SK, Cornish, T, Alpini, G, Bronk, S, Pan, D & Anders, RA 2012, 'Yes-associated protein regulates the hepatic response after bile duct ligation', Hepatology, vol. 56, no. 3, pp. 1097-1107. https://doi.org/10.1002/hep.25769
Bai, Haibo ; Zhang, Nailing ; Xu, Yang ; Chen, Qian ; Khan, Mehtab ; Potter, James John ; Nayar, Suresh K. ; Cornish, Toby ; Alpini, Gianfranco ; Bronk, Steven ; Pan, Duojia ; Anders, Robert A. / Yes-associated protein regulates the hepatic response after bile duct ligation. In: Hepatology. 2012 ; Vol. 56, No. 3. pp. 1097-1107.
@article{0710068f81c04088bf963e5b1ced0b8e,
title = "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.",
author = "Haibo Bai and Nailing Zhang and Yang Xu and Qian Chen and Mehtab Khan and Potter, {James John} and Nayar, {Suresh K.} and Toby Cornish and Gianfranco Alpini and Steven Bronk and Duojia Pan and Anders, {Robert A}",
year = "2012",
month = "9",
doi = "10.1002/hep.25769",
language = "English (US)",
volume = "56",
pages = "1097--1107",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

TY - JOUR

T1 - Yes-associated protein regulates the hepatic response after bile duct ligation

AU - Bai, Haibo

AU - Zhang, Nailing

AU - Xu, Yang

AU - Chen, Qian

AU - Khan, Mehtab

AU - Potter, James John

AU - Nayar, Suresh K.

AU - Cornish, Toby

AU - Alpini, Gianfranco

AU - Bronk, Steven

AU - Pan, Duojia

AU - Anders, Robert A

PY - 2012/9

Y1 - 2012/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84865571180&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865571180&partnerID=8YFLogxK

U2 - 10.1002/hep.25769

DO - 10.1002/hep.25769

M3 - Article

C2 - 22886419

AN - SCOPUS:84865571180

VL - 56

SP - 1097

EP - 1107

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 3

ER -