{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T17:04:48Z","timestamp":1793898288823,"version":"4.8.0"},"reference-count":34,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","license":[{"start":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T00:00:00Z","timestamp":1658275200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Chronic cholestatic liver diseases are characterized by injury of the bile ducts and hepatocytes caused by accumulated bile acids (BAs) and inflammation. Wnt\/\u03b2\u2010catenin signaling is implicated in organ fibrosis; however, its role in cholestatic liver fibrosis remains unclear. Therefore, we explored the effect of a selective cAMP response element\u2010binding protein\u2010binding protein (CBP)\/\u03b2\u2010catenin inhibitor, PRI\u2010724, on murine cholestatic liver fibrosis. PRI\u2010724 suppressed liver fibrosis induced by multidrug resistance protein 2 knockout (KO), bile duct ligation, or a 3.5\u2010diethoxycarbonyl\u20101.4\u2010dihydrocollidine (DDC) diet; it also suppressed BA synthesis and macrophage infiltration. The expression of early growth response\u20101 (Egr\u20101), which plays a key role in BA synthesis, was increased in the hepatocytes of patients with cholestatic liver disease. PRI\u2010724 inhibited Egr\u20101 expression induced by cholestasis, and adenoviral shEgr\u20101\u2010mediated <jats:italic toggle=\"yes\">Egr\u20101<\/jats:italic> knockdown suppressed BA synthesis and fibrosis in DDC diet\u2013fed mice, suggesting that PRI\u2010724 exerts its effects, at least in part, by suppressing Egr\u20101 expression in hepatocytes. Hepatocyte\u2010specific CBP KO in mice suppressed BA synthesis, liver injury, and fibrosis, whereas hepatocyte\u2010specific KO of P300, a CBP homolog, exacerbated DDC\u2010induced fibrosis. Intrahepatic Egr\u20101 expression was also decreased in hepatocyte\u2010specific CBP\u2010KO mice and increased in P300\u2010KO mice, indicating that Egr\u20101 is located downstream of CBP\/\u03b2\u2010catenin signaling. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: PRI\u2010724 inhibits cholestatic liver injury and fibrosis by inhibiting BA synthesis in hepatocytes. These results highlight the therapeutic effect of CBP\/\u03b2\u2010catenin inhibition in cholestatic liver diseases.<\/jats:p>","DOI":"10.1002\/hep4.2043","type":"journal-article","created":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T07:11:28Z","timestamp":1658301088000},"page":"2732-2747","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":22,"title":["Inhibition of CBP\/\u03b2\u2010catenin signaling ameliorated fibrosis in cholestatic liver disease"],"prefix":"10.1097","volume":"6","author":[{"given":"Masamichi","family":"Kimura","sequence":"first","affiliation":[{"name":"Department of Hepatology,Tokyo Metropolitan Cancer and Infectious Diseases Center,Komagome Hospital,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Nishikawa","sequence":"additional","affiliation":[{"name":"Department of Hepatology,Tokyo Metropolitan Cancer and Infectious Diseases Center,Komagome Hospital,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Osawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology,International University of Health and Welfare Hospital,Nasushiobara,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Imamura","sequence":"additional","affiliation":[{"name":"Department of Hepatology,Tokyo Metropolitan Cancer and Infectious Diseases Center,Komagome Hospital,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenzaburo","family":"Yamaji","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Cell Biology,Tokyo Metropolitan Institute of Medical Science,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Harada","sequence":"additional","affiliation":[{"name":"Department of Human Pathology,Kanazawa University Graduate School of Medicine,Kanazawa,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Yatsuhashi","sequence":"additional","affiliation":[{"name":"Clinical Research Center,National Hospital Organization Nagasaki Medical Center,Omura,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazumoto","family":"Murata","sequence":"additional","affiliation":[{"name":"Division of Virology,Department of Infection and Immunity,Jichi Medical University School of Medicine,Tochigi,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouichi","family":"Miura","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology,Department of Medicine,Jichi Medical University,Tochigi,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Medicine,Teikyo University School of Medicine,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Kanto","sequence":"additional","affiliation":[{"name":"The Research Center for Hepatitis and Immunology,National Center for Global Health and Medicine,Ichikawa,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michinori","family":"Kohara","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Cell Biology,Tokyo Metropolitan Institute of Medical Science,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terumi","family":"Kamisawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology,Tokyo Metropolitan Cancer and Infectious Diseases Center,Komagome Hospital,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9352-4721","authenticated-orcid":false,"given":"Kiminori","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Hepatology,Tokyo Metropolitan Cancer and Infectious Diseases Center,Komagome Hospital,Tokyo,Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2022,7,20]]},"reference":[{"key":"hep42043-bib-0001-20241127","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1016\/S0140-6736(20)31607-X","article-title":"Primary biliary cholangitis","volume":"396","year":"2020","journal-title":"Lancet"},{"key":"hep42043-bib-0002-20241127","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1056\/NEJM199405123301903","article-title":"Ursodiol for the long\u2010term treatment of primary biliary cirrhosis. 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