{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T21:36:31Z","timestamp":1790285791817,"version":"4.1.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":11,"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":[[2016,2]]},"abstract":"<jats:p>\n                    Deficiency of multidrug resistance 2 (mdr2), a canalicular phospholipid floppase, leads to excretion of low\u2010phospholipid \u201ctoxic\u201d bile causing progressive cholestasis. We hypothesize that pharmacological inhibition of the ileal, apical sodium\u2010dependent bile acid transporter (ASBT), blocks progression of sclerosing cholangitis in mdr2\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice. Thirty\u2010day\u2010old, female mdr2\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice were fed high\u2010fat chow containing 0.006% SC\u2010435, a minimally absorbed, potent inhibitor of ASBT, providing, on average, 11 mg\/kg\/day of compound. Bile acids (BAs) and phospholipids were measured by mass spectrometry.\n                  <\/jats:p>\n                  <jats:p>\n                    Compared with untreated mdr2\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice, SC\u2010435 treatment for 14 days increased fecal BA excretion by 8\u2010fold, lowered total BA concentration in liver by 65%, reduced total BA and individual hydrophobic BA concentrations in serum by &gt;98%, and decreased plasma alanine aminotransferase, total bilirubin, and serum alkaline phosphatase levels by 86%, 93%, and 55%, respectively. Liver histology of sclerosing cholangitis improved, and extent of fibrosis decreased concomitant with reduction of hepatic profibrogenic gene expression. Biliary BA concentrations significantly decreased and phospholipids remained low and unchanged with treatment. The phosphatidylcholine (PC)\/BA ratio in treated mice corrected toward a ratio of 0.28 found in wild\u2010type mice, indicating decreased bile toxicity. Hepatic RNA sequencing studies revealed up\u2010regulation of putative anti\u2010inflammatory and antifibrogenic genes, including\n                    <jats:italic toggle=\"yes\">Ppara<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Igf1<\/jats:italic>\n                    , and down\u2010regulation of several proinflammatory genes, including\n                    <jats:italic toggle=\"yes\">Ccl2<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Lcn2<\/jats:italic>\n                    , implicated in leukocyte recruitment. Flow cytometric analysis revealed significant reduction of frequencies of hepatic CD11b\n                    <jats:sup>+<\/jats:sup>\n                    F4\/80\n                    <jats:sup>+<\/jats:sup>\n                    Kupffer cells and CD11b\n                    <jats:sup>+<\/jats:sup>\n                    Gr1\n                    <jats:sup>+<\/jats:sup>\n                    neutrophils, accompanied by expansion of anti\u2010inflammatory Ly6C\n                    <jats:sup>\u2013<\/jats:sup>\n                    monocytes in treated mdr2\n                    <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    mice.\n                    <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>\n                    : Inhibition of ASBT reduces BA pool size and retention of hydrophobic BA, favorably alters the biliary PC\/BA ratio, profoundly changes the hepatic transcriptome, attenuates recruitment of leukocytes, and abrogates progression of murine sclerosing cholangitis. (H\n                    <jats:sc>epatology<\/jats:sc>\n                    2016;63:512\u2013523)\n                  <\/jats:p>","DOI":"10.1002\/hep.27973","type":"journal-article","created":{"date-parts":[[2015,7,14]],"date-time":"2015-07-14T09:48:15Z","timestamp":1436867295000},"page":"512-523","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":126,"title":["Pharmacological inhibition of apical sodium\u2010dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice"],"prefix":"10.1097","volume":"63","author":[{"given":"Alexander G.","family":"Miethke","sequence":"first","affiliation":[{"name":"Division of Pediatric Gastroenterology,Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center,Cincinnati,OH"},{"name":"Department of Pediatrics,University of Cincinnati College of Medicine,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wujuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Pathology and Laboratory Medicine,Cincinnati Children's Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Simmons","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology,Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy E.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology,Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Shi","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology,Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiva Kumar","family":"Shanmukhappa","sequence":"additional","affiliation":[{"name":"Division of Pathology and Laboratory Medicine,Cincinnati Children's Hospital Medical Center,Cincinnati,OH"},{"name":"Department of Pediatrics,University of Cincinnati College of Medicine,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebekah","family":"Karns","sequence":"additional","affiliation":[{"name":"Division of Biomedical Informatics,Cincinnati Children's Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shana","family":"White","sequence":"additional","affiliation":[{"name":"Division of Biomedical Informatics,Cincinnati Children's Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil G.","family":"Jegga","sequence":"additional","affiliation":[{"name":"Division of Biomedical Informatics,Cincinnati Children's Hospital Medical Center,Cincinnati,OH"},{"name":"Department of Pediatrics,University of Cincinnati College of Medicine,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine S.","family":"Lages","sequence":"additional","affiliation":[{"name":"Division of Pediatric Gastroenterology,Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephenson","family":"Nkinin","sequence":"additional","affiliation":[{"name":"Division of Pathology and Laboratory Medicine,Cincinnati Children's Hospital Medical Center,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley T.","family":"Keller","sequence":"additional","affiliation":[{"name":"Consultant to Shire plc,San Diego,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth D.R.","family":"Setchell","sequence":"additional","affiliation":[{"name":"Division of Pathology and Laboratory Medicine,Cincinnati Children's Hospital Medical Center,Cincinnati,OH"},{"name":"Department of Pediatrics,University of Cincinnati College of Medicine,Cincinnati,OH"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2015,8,21]]},"reference":[{"issue":"1 Suppl","key":"hep27973-bib-0001-20241017","first-page":"S25","article-title":"New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond","volume":"62","year":"2015","journal-title":"J Hepatol"},{"key":"hep27973-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1053\/j.gastro.2010.09.004","article-title":"Pathogenesis of cholestatic liver disease and therapeutic approaches","volume":"139","year":"2010","journal-title":"Gastroenterology"},{"key":"hep27973-bib-0003-20241017","article-title":"On fibrates and cholestasis: a review","year":"2015","journal-title":"Hepatology"},{"key":"hep27973-bib-0004-20241017","first-page":"1725","article-title":"Apoptosis and hepatobiliary disease","volume":"21","year":"1995","journal-title":"Hepatology"},{"key":"hep27973-bib-0005-20241017","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1053\/j.gastro.2009.11.046","article-title":"Genome\u2010wide association analysis in primary sclerosing cholangitis","volume":"138","year":"2010","journal-title":"Gastroenterology"},{"key":"hep27973-bib-0006-20241017","doi-asserted-by":"crossref","first-page":"10343","DOI":"10.1021\/jm501052c","article-title":"G\u2010protein\u2010coupled bile acid receptor 1 (GPBAR1, TGR5) agonists reduce the production of pro\u2010inflammatory cytokines and stabilize the alternative macrophage phenotype","volume":"57","year":"2014","journal-title":"J Med Chem"},{"key":"hep27973-bib-0007-20241017","first-page":"4242","article-title":"Liver diseases related to MDR3 (ABCB4) gene deficiency","volume":"14","year":"2009","journal-title":"Front Biosci"},{"key":"hep27973-bib-0008-20241017","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1159\/000282072","article-title":"New insights into autoimmune cholangitis through animal models","volume":"28","year":"2010","journal-title":"Dig Dis"},{"key":"hep27973-bib-0009-20241017","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1002\/hep.20022","article-title":"Spontaneous cholecysto\u2010 and hepatolithiasis in Mdr2\u2013\/\u2013 mice: a model for low phospholipid\u2010associated cholelithiasis","volume":"39","year":"2004","journal-title":"Hepatology"},{"key":"hep27973-bib-0010-20241017","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":"hep27973-bib-0011-20241017","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1053\/j.gastro.2005.10.018","article-title":"24\u2010norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice","volume":"130","year":"2006","journal-title":"Gastroenterology"},{"key":"hep27973-bib-0012-20241017","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1002\/hep.27408","article-title":"Growth hormone resistance exacerbates cholestasis\u2010induced murine liver fibrosis","volume":"61","year":"2015","journal-title":"Hepatology"},{"key":"hep27973-bib-0013-20241017","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1124\/jpet.102.038711","article-title":"Fernandez ML. 1\u2010[4\u2010[4[(4R,5R)\u22123,3\u2010Dibutyl\u20107\u2010(dimethylamino)\u22122,3,4,5\u2010tetrahydro\u20104\u2010hydroxy\u20101,1\u2010di oxido\u20101\u2010benzothiepin\u20105\u2010yl]phenoxy]butyl]\u20104\u2010aza\u20101\u2010azoniabicyclo[2.2.2] octane methanesulfonate (SC\u2010435), an ileal apical sodium\u2010codependent bile acid transporter inhibitor alters hepatic cholesterol metabolism and lowers plasma low\u2010density lipoprotein\u2010cholesterol concentrations in guinea pigs","volume":"303","year":"2002","journal-title":"J Pharmacol Exp Ther"},{"key":"hep27973-bib-0014-20241017","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1002\/hep.25662","article-title":"Regulatory T cells control the CD8 adaptive immune response at the time of ductal obstruction in experimental biliary atresia","volume":"56","year":"2012","journal-title":"Hepatology"},{"key":"hep27973-bib-0015-20241017","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1194\/jlr.D800041-JLR200","article-title":"Improved analysis of bile acids in tissues and intestinal contents of rats using LC\/ESI\u2010MS","volume":"50","year":"2009","journal-title":"J Lipid Res"},{"key":"hep27973-bib-0016-20241017","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1002\/hep.24047","article-title":"Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct\u2010ligated rats and human hepatic cells","volume":"53","year":"2011","journal-title":"Hepatology"},{"key":"hep27973-bib-0017-20241017","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1177\/0192623311436177","article-title":"Immunophenotypic alterations in resident immune cells and myocardial fibrosis in the aging rhesus macaque (Macaca mulatta) heart","volume":"40","year":"2012","journal-title":"Toxicol Pathol"},{"key":"hep27973-bib-0018-20241017","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1093\/bioinformatics\/btp120","article-title":"TopHat: discovering splice junctions with RNA\u2010Seq","volume":"25","year":"2009","journal-title":"Bioinformatics"},{"key":"hep27973-bib-0019-20241017","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1038\/nbt.1621","article-title":"Transcript assembly and quantification by RNA\u2010Seq reveals unannotated transcripts and isoform switching during cell differentiation","volume":"28","year":"2010","journal-title":"Nat Biotechnol"},{"key":"hep27973-bib-0020-20241017","doi-asserted-by":"crossref","first-page":"W305","DOI":"10.1093\/nar\/gkp427","article-title":"ToppGene Suite for gene list enrichment analysis and candidate gene prioritization","volume":"37","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"hep27973-bib-0021-20241017","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1194\/jlr.D200043-JLR200","article-title":"Monitoring hepatic cholesterol 7alpha\u2010hydroxylase activity by assay of the stable bile acid intermediate 7alpha\u2010hydroxy\u20104\u2010cholesten\u20103\u2010one in peripheral blood","volume":"44","year":"2003","journal-title":"J Lipid Res"},{"key":"hep27973-bib-0022-20241017","first-page":"17S","article-title":"Bile acid secretion, bile flow and biliary lipid secretion in humans","volume":"12","year":"1990","journal-title":"Hepatology"},{"key":"hep27973-bib-0023-20241017","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1146\/annurev.me.18.020167.002001","article-title":"Detergent properties of bile salts: correlation with physiological function","volume":"18","year":"1967","journal-title":"Annu Rev Med"},{"key":"hep27973-bib-0024-20241017","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/S0022-2275(20)37603-3","article-title":"Complete mapping of crystallization pathways during cholesterol precipitation from model bile: influence of physical\u2010chemical variables of pathophysiologic relevance and identification of a stable liquid crystalline state in cold, dilute and hydrophilic bile salt\u2010containing systems","volume":"37","year":"1996","journal-title":"J Lipid Res"},{"key":"hep27973-bib-0025-20241017","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.jcpa.2014.05.003","article-title":"Expression of nestin in remodelling of alpha\u2010naphthylisothiocyanate\u2010induced acute bile duct injury in rats","volume":"151","year":"2014","journal-title":"J Comp Pathol"},{"key":"hep27973-bib-0026-20241017","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.atherosclerosis.2003.08.019","article-title":"SC\u2010435, an ileal apical sodium co\u2010dependent bile acid transporter (ASBT) inhibitor lowers plasma cholesterol and reduces atherosclerosis in guinea pigs","volume":"171","year":"2003","journal-title":"Atherosclerosis"},{"key":"hep27973-bib-0027-20241017","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1111\/j.1478-3231.2005.01036.x","article-title":"Bile duct proliferation associated with bile salt\u2010induced hypercholeresis in Mdr2 P\u2010glycoprotein\u2010deficient mice","volume":"25","year":"2005","journal-title":"Liver Int"},{"key":"hep27973-bib-0028-20241017","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/S0168-8278(97)80020-7","article-title":"The role of bile salt composition in liver pathology of mdr2 (\u2010\/\u2010) mice: differences between males and females","volume":"26","year":"1997","journal-title":"J Hepatol"},{"key":"hep27973-bib-0029-20241017","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1042\/bj1880321","article-title":"Effects of bile salts on the plasma membranes of isolated rat hepatocytes","volume":"188","year":"1980","journal-title":"Biochem J"},{"key":"hep27973-bib-0030-20241017","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1172\/JCI4765","article-title":"Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas","volume":"103","year":"1999","journal-title":"J Clin Invest"},{"key":"hep27973-bib-0031-20241017","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1053\/jhep.2001.22702","article-title":"Bile acid\u2010induced rat hepatocyte apoptosis is inhibited by antioxidants and blockers of the mitochondrial permeability transition","volume":"33","year":"2001","journal-title":"Hepatology"},{"key":"hep27973-bib-0032-20241017","doi-asserted-by":"crossref","first-page":"3496","DOI":"10.3748\/wjg.v12.i22.3496","article-title":"Cholangiocyte anion exchange and biliary bicarbonate excretion","volume":"12","year":"2006","journal-title":"World J Gastroenterol"},{"key":"hep27973-bib-0033-20241017","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1002\/hep.23810","article-title":"The biliary HCO(3)(\u2010) umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies","volume":"52","year":"2010","journal-title":"Hepatology"},{"key":"hep27973-bib-0034-20241017","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1016\/S0024-3205(02)02408-6","article-title":"Effects of bile acids on biliary epithelial cells: proliferation, cytotoxicity, and cytokine secretion","volume":"72","year":"2003","journal-title":"Life Sci"},{"key":"hep27973-bib-0035-20241017","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1002\/hep.22637","article-title":"Fibrogenesis in pediatric cholestatic liver disease: role of taurocholate and hepatocyte\u2010derived monocyte chemotaxis protein\u20101 in hepatic stellate cell recruitment","volume":"49","year":"2009","journal-title":"Hepatology"},{"key":"hep27973-bib-0036-20241017","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.jprot.2012.11.021","article-title":"Proteomic profiling in Lipocalin 2 deficient mice under normal and inflammatory conditions","volume":"78","year":"2013","journal-title":"J Proteomics"},{"key":"hep27973-bib-0037-20241017","doi-asserted-by":"crossref","first-page":"11761","DOI":"10.1074\/jbc.M112.446575","article-title":"Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease","volume":"288","year":"2013","journal-title":"J Biol Chem"},{"key":"hep27973-bib-0038-20241017","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/srep00430","article-title":"TGR5 potentiates GLP\u20101 secretion in response to anionic exchange resins","volume":"2","year":"2012","journal-title":"Sci Rep"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.27973","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.27973","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201602000-00023","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T19:37:34Z","timestamp":1729193854000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201602000-00023"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,21]]},"references-count":38,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2016]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.27973","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.725633368.793516315","asserted-by":"object"}]},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,21]]},"assertion":[{"value":"2015-03-25","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-07-07","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}