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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Haibo
authors.initials: H
authors.lastname: Bai
authors.forename: Nailing
authors.initials: N
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.forename: Mehtab
authors.initials: M
authors.lastname: Khan
authors.forename: James J
authors.initials: JJ
authors.lastname: Potter
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Nayar
authors.forename: Toby
authors.initials: T
authors.lastname: Cornish
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Alpini
authors.forename: Steven
authors.initials: S
authors.lastname: Bronk
authors.forename: Duojia
authors.initials: D
authors.lastname: Pan
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000166:cytology*; D002779:Cholestasis / Q000150:complications*; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D008026:Ligation; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D051575:Proto-Oncogene Proteins c-yes / Q000502:physiology*
chemical_list: D051575:Proto-Oncogene Proteins c-yes