{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T23:29:55Z","timestamp":1791415795344,"version":"4.3.3"},"reference-count":54,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2012,8,8]],"date-time":"2012-08-08T00:00:00Z","timestamp":1344384000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2012,9,1]],"date-time":"2012-09-01T00:00:00Z","timestamp":1346457600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,9]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>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<\/jats:bold>\n                                 <jats:bold>\n                                    Yap\n                                 <\/jats:bold>\n                                 <jats:bold>conditional deletion in mice. Ablating<\/jats:bold>\n                                 <jats:bold>\n                                    Yap\n                                 <\/jats:bold>\n                                 <jats:bold>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<\/jats:bold>\n                                 <jats:bold>\n                                    Yap\n                                 <\/jats:bold>-<jats:bold>deficient livers showed reduced proliferation in response to epidermal growth factor<\/jats:bold>\n                                 <jats:bold>\n                                    in vitro\n                                 <\/jats:bold>. <jats:bold>Finally, we demonstrated that YAP likely mediates its biological effects through the modulation of<\/jats:bold>\n                                 <jats:bold>\n                                    Survivin\n                                 <\/jats:bold>\n                                 <jats:bold>expression.<\/jats:bold>\n                                 <jats:bold>\n                                    Conclusion\n                                 <\/jats:bold>: <jats:bold>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.<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.25769","type":"journal-article","created":{"date-parts":[[2012,8,8]],"date-time":"2012-08-08T13:02:07Z","timestamp":1344430927000},"page":"1097-1107","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":158,"title":["Yes-associated protein regulates the hepatic response after bile duct ligation"],"prefix":"10.1097","volume":"56","author":[{"given":"Haibo","family":"Bai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nailing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehtab","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James J.","family":"Potter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh K.","family":"Nayar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toby","family":"Cornish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianfranco","family":"Alpini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Bronk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duojia","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Anders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-33-20250207","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1053\/j.gastro.2004.08.006","article-title":"The cholangiopathies: disorders of biliary epithelia.","volume":"127","author":"Lazaridis","year":"2004","journal-title":"Gastroenterology"},{"key":"R2-33-20250207","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.mam.2007.09.007","article-title":"New insights on the molecular and cell biology of human cholangiopathies.","volume":"29","author":"Alvaro","year":"2008","journal-title":"Mol Aspects Med"},{"key":"R3-33-20250207","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1002\/hep.1840120523","article-title":"Hepatic injury induced by bile salts: correlation between biochemical and morphological events.","volume":"12","author":"Schmucker","year":"1990","journal-title":"HEPATOLOGY"},{"key":"R4-33-20250207","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1172\/JCI24282","article-title":"Liver fibrosis.","volume":"115","author":"Bataller","year":"2005","journal-title":"J Clin Invest"},{"key":"R5-33-20250207","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1053\/j.gastro.2009.02.051","article-title":"Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9.","volume":"136","author":"Antoniou","year":"2009","journal-title":"Gastroenterology"},{"key":"R6-33-20250207","doi-asserted-by":"crossref","first-page":"e1851","DOI":"10.1371\/journal.pone.0001851","article-title":"Notch signaling regulates bile duct morphogenesis in mice.","volume":"3","author":"Lozier","year":"2008","journal-title":"PLoS ONE"},{"key":"R7-33-20250207","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/labinvest.3700537","article-title":"Hedgehogmediated mesenchymalepithelial interactions modulate hepatic response to bile duct ligation.","volume":"87","author":"Omenetti","year":"2007","journal-title":"Lab Invest"},{"key":"R8-33-20250207","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1006\/jsre.1999.5574","article-title":"GUDC inhibits cytochrome c release from human cholangiocyte mitochondria.","volume":"83","author":"Que","year":"1999","journal-title":"J Surg Res"},{"key":"R9-33-20250207","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1038\/labinvest.2009.103","article-title":"Foxl1 promotes liver repair following cholestatic injury in mice.","volume":"89","author":"Sackett","year":"2009","journal-title":"Lab Invest"},{"key":"R10-33-20250207","doi-asserted-by":"crossref","first-page":"15164","DOI":"10.1074\/jbc.M010484200","article-title":"Physical interaction with Yesassociated protein enhances p73 transcriptional activity.","volume":"276","author":"Strano","year":"2001","journal-title":"J Biol Chem"},{"key":"R11-33-20250207","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.1093\/emboj\/18.9.2551","article-title":"A WW domaincontaining yesassociated protein (YAP) is a novel transcriptional coactivator.","volume":"18","author":"Yagi","year":"1999","journal-title":"EMBO J"},{"key":"R12-33-20250207","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1101\/gad.888601","article-title":"TEADTEF transcription factors utilize the activation domain of YAP65, a SrcYesassociated protein localized in the cytoplasm.","volume":"15","author":"Vassilev","year":"2001","journal-title":"Genes Dev"},{"key":"R13-33-20250207","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1016\/j.cell.2007.07.019","article-title":"Elucidation of a universal sizecontrol mechanism in Drosophila and mammals.","volume":"130","author":"Dong","year":"2007","journal-title":"Cell"},{"key":"R14-33-20250207","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.devcel.2010.09.011","article-title":"The hippo signaling pathway in development and cancer.","volume":"19","author":"Pan","year":"2010","journal-title":"Dev Cell"},{"key":"R15-33-20250207","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1101\/gad.1602907","article-title":"Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.","volume":"21","author":"Zhao","year":"2007","journal-title":"Genes Dev"},{"key":"R16-33-20250207","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1038\/ncb1993","article-title":"YAPdependent induction of amphiregulin identifies a noncellautonomous component of the Hippo pathway.","volume":"11","author":"Zhang","year":"2009","journal-title":"Nat Cell Biol"},{"key":"R17-33-20250207","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1016\/j.cub.2007.10.039","article-title":"YAP1 increases organ size and expands undifferentiated progenitor cells.","volume":"17","author":"Camargo","year":"2007","journal-title":"Curr Biol"},{"key":"R18-33-20250207","doi-asserted-by":"crossref","first-page":"8248","DOI":"10.1073\/pnas.0912203107","article-title":"The HippoSalvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis.","volume":"107","author":"Lee","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R19-33-20250207","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1073\/pnas.0911427107","article-title":"Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver.","volume":"107","author":"Lu","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R20-33-20250207","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1073\/pnas.0911409107","article-title":"Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression.","volume":"107","author":"Song","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R21-33-20250207","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.devcel.2010.06.015","article-title":"The MerlinNF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals.","volume":"19","author":"Zhang","year":"2010","journal-title":"Dev Cell"},{"key":"R22-33-20250207","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.ccr.2009.09.026","article-title":"Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene.","volume":"16","author":"Zhou","year":"2009","journal-title":"Cancer Cell"},{"key":"R23-33-20250207","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/sj.bjc.6606011","article-title":"Mst12 signalling to Yap: gatekeeper for liver size and tumour development.","volume":"104","author":"Avruch","year":"2011","journal-title":"Br J Cancer"},{"key":"R24-33-20250207","doi-asserted-by":"crossref","first-page":"7561","DOI":"10.1158\/0008-5472.CAN-05-1513","article-title":"Multiple microalterations detected at high frequency in oral cancer.","volume":"65","author":"Baldwin","year":"2005","journal-title":"Cancer Res"},{"key":"R25-33-20250207","doi-asserted-by":"crossref","first-page":"12405","DOI":"10.1073\/pnas.0605579103","article-title":"Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon.","volume":"103","author":"Overholtzer","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R26-33-20250207","doi-asserted-by":"crossref","first-page":"4232","DOI":"10.1038\/sj.onc.1208601","article-title":"Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma.","volume":"24","author":"Snijders","year":"2005","journal-title":"Oncogene"},{"key":"R27-33-20250207","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.cell.2006.05.030","article-title":"Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach.","volume":"125","author":"Zender","year":"2006","journal-title":"Cell"},{"key":"R28-33-20250207","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1593\/neo.04586","article-title":"Arraybased comparative genomic hybridization identifies localized DNA amplifications and homozygous deletions in pancreatic cancer.","volume":"7","author":"Bashyam","year":"2005","journal-title":"Neoplasia"},{"key":"R29-33-20250207","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1093\/hmg\/ddg083","article-title":"A comprehensive search for DNA amplification in lung cancer identifies inhibitors of apoptosis cIAP1 and cIAP2 as candidate oncogenes.","volume":"12","author":"Dai","year":"2003","journal-title":"Hum Mol Genet"},{"key":"R30-33-20250207","first-page":"6629","article-title":"Identification of cIAP1 as a candidate target gene within an amplicon at 11q22 in esophageal squamous cell carcinomas.","volume":"61","author":"Imoto","year":"2001","journal-title":"Cancer Res"},{"key":"R31-33-20250207","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.1101\/gad.1824509","article-title":"YAP1 is amplified and upregulated in hedgehogassociated medulloblastomas and mediates Sonic hedgehogdriven neural precursor proliferation.","volume":"23","author":"Fernandez","year":"2009","journal-title":"Genes Dev"},{"key":"R32-33-20250207","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1016\/j.humpath.2008.04.012","article-title":"Expression of Yesassociated protein in common solid tumors.","volume":"39","author":"Steinhardt","year":"2008","journal-title":"Hum Pathol"},{"key":"R33-33-20250207","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/BF00432479","article-title":"Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis).","volume":"379","author":"Ludwig","year":"1978","journal-title":"Virchows Arch A Pathol Anat Histol"},{"key":"R34-33-20250207","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1126\/science.7660125","article-title":"Inducible gene targeting in mice.","volume":"269","author":"Kuhn","year":"1995","journal-title":"Science"},{"key":"R35-33-20250207","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1159\/000129252","article-title":"The role of bile and bile acids in bacterial translocation in obstructive jaundice in rats.","volume":"25","author":"Ding","year":"1993","journal-title":"Eur Surg Res"},{"key":"R36-33-20250207","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1136\/gut.2006.097170","article-title":"Cholestasis protects the liver from ischaemic injury and postischaemic inflammation in the mouse.","volume":"56","author":"Georgiev","year":"2007","journal-title":"Gut"},{"key":"R37-33-20250207","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/BF02623304","article-title":"Use of a lowspeed, isodensity percoll centrifugation method to increase the viability of isolated rat hepatocyte preparations.","volume":"22","author":"Kreamer","year":"1986","journal-title":"In Vitro Cell Dev Biol"},{"key":"R38-33-20250207","first-page":"303","article-title":"Development and characterization of polarized primary cultures of rat intrahepatic bile duct epithelial cells.","volume":"74","author":"Vroman","year":"1996","journal-title":"Lab Invest"},{"key":"R39-33-20250207","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.dld.2010.01.008","article-title":"Recent advances in the regulation of cholangiocyte proliferation and function during extrahepatic cholestasis.","volume":"42","author":"Glaser","year":"2010","journal-title":"Dig Liver Dis"},{"key":"R40-33-20250207","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1002\/bjs.6050","article-title":"Characterization of timerelated changes after experimental bile duct ligation.","volume":"95","author":"Georgiev","year":"2008","journal-title":"Br J Surg"},{"key":"R41-33-20250207","doi-asserted-by":"crossref","first-page":"7257","DOI":"10.1073\/pnas.92.16.7257","article-title":"Upregulation of class I major histocompatibility complex antigens by interferon gamma is necessary for Tcellmediated elimination of recombinant adenovirusinfected hepatocytes in vivo.","volume":"92","author":"Yang","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R42-33-20250207","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1002\/hep.20130","article-title":"Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers.","volume":"39","author":"Roskams","year":"2004","journal-title":"HEPATOLOGY"},{"key":"R43-33-20250207","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/S0344-0338(11)80870-8","article-title":"Ductular reaction in the liver.","volume":"191","author":"Desmet","year":"1995","journal-title":"Pathol Res Pract"},{"key":"R44-33-20250207","doi-asserted-by":"crossref","first-page":"4477","DOI":"10.1073\/pnas.0306068101","article-title":"Hepatocyte growth factorcmet signaling pathway is required for efficient liver regeneration and repair.","volume":"101","author":"Huh","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R45-33-20250207","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1055\/s-2007-991510","article-title":"Death receptormediated liver injury.","volume":"27","author":"Akazawa","year":"2007","journal-title":"Semin Liver Dis"},{"key":"R46-33-20250207","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1002\/hep.22381","article-title":"Liverspecific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice.","volume":"48","author":"Geisler","year":"2008","journal-title":"HEPATOLOGY"},{"key":"R47-33-20250207","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nm0897-917","article-title":"A novel antiapoptosis gene, survivin, expressed in cancer and lymphoma.","volume":"3","author":"Ambrosini","year":"1997","journal-title":"Nat Med"},{"key":"R48-33-20250207","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.ceb.2006.08.015","article-title":"The case for survivin as a regulator of microtubule dynamics and celldeath decisions.","volume":"18","author":"Altieri","year":"2006","journal-title":"Curr Opin Cell Biol"},{"key":"R49-33-20250207","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1101\/gad.1978810","article-title":"The Hippo signaling pathway restricts the oncogenic potential of an intestinal regeneration program.","volume":"24","author":"Cai","year":"2010","journal-title":"Genes Dev"},{"key":"R50-33-20250207","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1101\/gad.1938710","article-title":"Nf2Merlin controls progenitor homeostasis and tumorigensis in the liver.","volume":"24","author":"Benhamouche","year":"2010","journal-title":"Genes Dev"},{"key":"R52-33-20250207","first-page":"5315","article-title":"IAPfamily protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs.","volume":"58","author":"Tamm","year":"1998","journal-title":"Cancer Res"},{"key":"R53-33-20250207","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/S0960-9822(01)00238-X","article-title":"INCENP is required for proper targeting of Survivin to the centromeres and the anaphase spindle during mitosis.","volume":"11","author":"Wheatley","year":"2001","journal-title":"Curr Biol"},{"key":"R54-33-20250207","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/nrc2293","article-title":"Survivin, cancer networks and pathwaydirected drug discovery.","volume":"8","author":"Altieri","year":"2008","journal-title":"Nat Rev Cancer"},{"key":"R55-33-20250207","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1084\/jem.20032092","article-title":"Survivin loss in thymocytes triggers p53mediated growth arrest and p53independent cell death.","volume":"199","author":"Okada","year":"2004","journal-title":"J Exp Med"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.25769","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.25769","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.25769","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201209000-00033","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T16:52:16Z","timestamp":1738947136000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201209000-00033"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,9]]},"references-count":54,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2012]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.25769","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2012,9]]}}}