{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T14:34:59Z","timestamp":1779201299923,"version":"3.51.4"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","license":[{"start":{"date-parts":[[2022,6,12]],"date-time":"2022-06-12T00:00:00Z","timestamp":1654992000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2022,9]]},"abstract":"Abstract<\/jats:title>\n Bile salt export pump (Bsep<\/jats:italic>) (Abcb11)\n \u2212\/\u2212\n <\/jats:sup> mice are protected from acquired cholestatic injury due to metabolic preconditioning with a hydrophilic bile acid (BA) pool with formation of tetrahydroxylated bile acids (THBAs). We aimed to explore whether loss of Bsep<\/jats:italic> and subsequent elevation of THBA levels may have immunomodulatory effects, thus improving liver injury in the multidrug resistance protein 2 (Mdr2<\/jats:italic>) (Abcb4)<\/jats:italic>\n \n \u2212\/\u2212\n <\/jats:sup> mouse. Cholestatic liver injury in Mdr2<\/jats:italic>\n \n \u2212\/\u2212\n <\/jats:sup>\n Bsep<\/jats:italic>\n \n \u2212\/\u2212\n <\/jats:sup> double knockout (DKO), Mdr2<\/jats:italic>\n \n \u2212\/\u2212\n <\/jats:sup>, Bsep<\/jats:italic>\n \n \u2212\/\u2212\n <\/jats:sup>, and wild\u2010type mice was studied for comparison. Mdr2<\/jats:italic>\n \n \u2212\/\u2212\n <\/jats:sup> mice were treated with a THBA (3\u03b1,6\u03b1,7\u03b1,12\u03b1\u2010Tetrahydroxycholanoic acid). RNA\/protein expression of inflammatory\/fibrotic markers were investigated. Serum BA\u2010profiling was assessed by ultra\u2010performance liquid chromatography tandem mass spectrometry. Hepatic immune cell profile was quantified by flow cytometric analysis (FACS). In vitro<\/jats:italic>, the THBA effect on chenodeoxycholic acid (CDCA)\u2013induced inflammatory signaling in hepatocyte and cholangiocytes as well as lipopolysaccharide (LPS)\/interferon\u2010\u03b3 (IFN\u2010\u03b3)\u2013induced macrophage activation was analyzed. In contrast to Mdr2<\/jats:italic>\n \n \u2212\/\u2212\n <\/jats:sup>, DKO mice showed no features of sclerosing cholangitis. Sixty\u2010seven percent of serum BAs in DKO mice were polyhydroxylated (mostly THBAs), whereas Mdr2<\/jats:italic>\n \n \u2212\/\u2212\n <\/jats:sup> mice did not have these BAs. Compared with Mdr2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>, DKO animals were protected from hepatic inflammation\/fibrosis. THBA feeding in Mdr2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup> mice improved liver injury. FACS analysis in DKO and Mdr2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup> THBA\u2010fed mice showed changes of the hepatic immune cell profile towards an anti\u2010inflammatory pattern. Early growth response 1 (EGR1) protein expression was reduced in DKO and in Mdr2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup> THBA\u2010fed mice compared with Mdr2<\/jats:italic>\n \u2212\/\u2212<\/jats:sup> control mice. In vitro<\/jats:italic>, THBA\u2010reduced CDCA induced EGR1 protein and mRNA expression of inflammatory markers in hepatocytes and cholangiocytes. LPS\/IFN\u2010\u03b3\u2013induced macrophage activation was ameliorated by THBA. THBAs repress EGR1\u2010related key pro\u2010inflammatory pathways. Conclusion<\/jats:italic>: THBA and their downstream targets may represent a potential treatment strategy for cholestatic liver diseases.<\/jats:p>","DOI":"10.1002\/hep4.1998","type":"journal-article","created":{"date-parts":[[2022,6,12]],"date-time":"2022-06-12T17:39:55Z","timestamp":1655055595000},"page":"2368-2378","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":15,"title":["Tetrahydroxylated bile acids improve cholestatic liver and bile duct injury in the Mdr2\u2212\/\u2212 mouse model of sclerosing cholangitis via immunomodulatory effects"],"prefix":"10.1097","volume":"6","author":[{"given":"Claudia D.","family":"Fuchs","sequence":"first","affiliation":[{"name":"Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuel D.","family":"Dixon","sequence":"additional","affiliation":[{"name":"Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Hendrikx","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine,Medical University of Vienna,Vienna,Austria"},{"name":"Department of Molecular Genetics,Maastricht University,Maastricht,the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronika","family":"Mlitz","sequence":"additional","affiliation":[{"name":"Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annika","family":"Wahlstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine,Sahlgrenska Academy,University of Gothenburg,Gothenburg,Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcus","family":"St\u00e5hlman","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine,Sahlgrenska Academy,University of Gothenburg,Gothenburg,Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hubert","family":"Scharnagl","sequence":"additional","affiliation":[{"name":"Clinical Institute of Medical and Chemical Laboratory Diagnostics,Medical University of Graz,Graz,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatjana","family":"Stojakovic","sequence":"additional","affiliation":[{"name":"Clinical Institute of Medical and Chemical Laboratory Diagnostics,University Hospital Graz,Graz,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph J.","family":"Binder","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanns\u2010Ulrich","family":"Marschall","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Medicine,Sahlgrenska Academy,University of Gothenburg,Gothenburg,Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Trauner","sequence":"additional","affiliation":[{"name":"Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III,Medical University of Vienna,Vienna,Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2022,6,12]]},"reference":[{"key":"hep41998-bib-0001-20241118","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1016\/j.jhep.2014.02.006","article-title":"Characterization of animal models for primary sclerosing cholangitis (PSC)","volume":"60","year":"2014","journal-title":"J Hepatol"},{"key":"hep41998-bib-0002-20241118","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1053\/j.gastro.2004.04.009","article-title":"Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice","volume":"127","year":"2004","journal-title":"Gastroenterology"},{"key":"hep41998-bib-0003-20241118","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1053\/j.gastro.2004.08.006","article-title":"The cholangiopathies: disorders of biliary 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History"}},{"value":"2022-04-28","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}