{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T03:34:40Z","timestamp":1790739280489,"version":"4.1.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2019,12,31]],"date-time":"2019-12-31T00:00:00Z","timestamp":1577750400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2019,12,31]],"date-time":"2019-12-31T00:00:00Z","timestamp":1577750400000},"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":["Hepatology"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>The Wnt\/\u03b2\u2010catenin signaling pathway has a well\u2010described role in liver pathobiology. Its suppression was recently shown to decrease bile acid (BA) synthesis, thus preventing the development of cholestatic liver injury and fibrosis after bile duct ligation (BDL).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>To generalize these observations, we suppressed \u03b2\u2010catenin in Mdr2 knockout (KO) mice, which develop sclerosing cholangitis due to regurgitation of BA from leaky ducts. When \u03b2\u2010catenin was knocked down (KD) in KO for 2 weeks, hepatic and biliary injury were exacerbated in comparison to KO given placebo, as shown by serum biochemistry, ductular reaction, inflammation, and fibrosis. Simultaneously, KO\/KD livers displayed increased oxidative stress and senescence and an impaired regenerative response. Although the total liver BA levels were similar between KO\/KD and KO, there was significant dysregulation of BA transporters and BA detoxification\/synthesis enzymes in KO\/KD compared with KO alone. Multiphoton intravital microscopy revealed a mixing of blood and bile in the sinusoids, and validated the presence of increased serum BA in KO\/KD mice. Although hepatocyte junctions were intact, KO\/KD livers had significant canalicular defects, which resulted from loss of hepatocyte polarity. Thus, in contrast to the protective effect of \u03b2\u2010catenin KD in BDL model, \u03b2\u2010catenin KD in Mdr2 KO aggravated rather than alleviated injury by interfering with expression of BA transporters, hepatocyte polarity, canalicular structure, and the regenerative response.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>The resulting imbalance between ongoing injury and restitution led to worsening of the Mdr2 KO phenotype, suggesting caution in targeting \u03b2\u2010catenin globally for all cholestatic conditions.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.30927","type":"journal-article","created":{"date-parts":[[2019,9,6]],"date-time":"2019-09-06T08:00:56Z","timestamp":1567756856000},"page":"1732-1749","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":36,"title":["Wnt\/\u03b2\u2010Catenin Signaling Plays a Protective Role in the Mdr2 Knockout Murine Model of Cholestatic Liver Disease"],"prefix":"10.1097","volume":"71","author":[{"given":"Tirthadipa","family":"Pradhan\u2010Sundd","sequence":"first","affiliation":[{"name":"Department of Pathology,University of Pittsburgh School of Medicine,Pittsburgh,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karis","family":"Kosar","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Pittsburgh School of Medicine,Pittsburgh,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harvinder","family":"Saggi","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Pittsburgh School of Medicine,Pittsburgh,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Pittsburgh School of Medicine,Pittsburgh,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"Vats","sequence":"additional","affiliation":[{"name":"Vascular Medicine Institute,University of Pittsburgh School of Medicine,Pittsburgh,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Cornuet","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Pittsburgh School of Medicine,Pittsburgh,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Green","sequence":"additional","affiliation":[{"name":"Morehouse School of Medicine,Atlanta,GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sucha","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Pittsburgh School of Medicine,Pittsburgh,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Pittsburgh School of Medicine,Pittsburgh,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prithu","family":"Sundd","sequence":"additional","affiliation":[{"name":"Vascular Medicine Institute,University of Pittsburgh School of Medicine,Pittsburgh,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6051-5338","authenticated-orcid":false,"given":"Kari","family":"Nejak\u2010Bowen","sequence":"additional","affiliation":[{"name":"Department of Pathology,University of Pittsburgh School of Medicine,Pittsburgh,PA"},{"name":"Pittsburgh Liver Research Center,University of Pittsburgh School of 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