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Inhibition of intes...
Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis
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Baghdasaryan, A. (author)
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Fuchs, C. D. (author)
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Osterreicher, C. H. (author)
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Lemberger, U. J. (author)
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Halilbasic, E. (author)
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Pahlman, I. (author)
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Graffner, H. (author)
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Krones, E. (author)
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Fickert, P. (author)
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- Wahlström, Annika, 1975 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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- Ståhlman, Marcus, 1975 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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Paumgartner, G. (author)
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- Marschall, Hanns-Ulrich, 1954 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Institute of Medicine, Department of Molecular and Clinical Medicine
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Trauner, M. (author)
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(creator_code:org_t)
- Elsevier BV, 2016
- 2016
- English.
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In: Journal of Hepatology. - : Elsevier BV. - 0168-8278. ; 64:3, s. 674-681
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Abstract
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- Background and Aims: Approximately 95% of bile acids (BAs) excreted into bile are reabsorbed in the gut and circulate back to the liver for further biliary secretion. Therefore, pharmacological inhibition of the ileal apical sodium-dependent BA transporter (ASBT/SLC10A2) may protect against BA-mediated cholestatic liver and bile duct injury. Methods: Eight week old Mdr2(-/-) (Abcb4(-/-)) mice (model of cholestatic liver injury and sclerosing cholangitis) received either a diet supplemented with A4250 (0.01% w/w) - a highly potent and selective ASBT inhibitor - or a chow diet. Liver injury was assessed biochemically and histologically after 4 weeks of A4250 treatment. Expression profiles of genes involved in BA homeostasis, inflammation and fibrosis were assessed via RT-PCR from liver and ileum homogenates. Intestinal inflammation was assessed by RNA expression profiling and immunohistochemistry. Bile flow and composition, as well as biliary and fecal BA profiles were analyzed after 1 week of ASBT inhibitor feeding. Results: A4250 improved sclerosing cholangitis in Mdr2(-/-) mice and significantly reduced serum alanine aminotransferase, alkaline phosphatase and BAs levels, hepatic expression of proinflammatory (Tnf-alpha, Vcam1, Mcp-1) and pro-fibrogenic (Col1a1, Col1a2) genes and bile duct proliferation (mRNA and immunohistochemistry for cytokeratin 19 (CK19)). Furthermore, A4250 significantly reduced bile flow and biliary BA output, which correlated with reduced Bsep transcription, while Ntcp and Cyp7a1 were induced. Importantly A4250 significantly reduced biliary BA secretion but preserved HCO3- and biliary phospholipid secretion resulting in an increased HCO3-/BA and PL/BA ratio. In addition, A4250 profoundly increased fecal BA excretion without causing diarrhea and altered BA pool composition, resulting in diminished concentrations of primary BAs tauro-beta-muricholic acid and taurocholic acid. Conclusions: Pharmacological ASBT inhibition attenuates cholestatic liver and bile duct injury by reducing biliary BA concentrations in mice. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Gastroenterologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Gastroenterology and Hepatology (hsv//eng)
Keyword
- Sodium-dependent BA transporter (ASBT/SLC10A2)
- Sclerosing
- Cholangitis
- Liver and bile duct injury
- glucagon-like peptide-1
- farnesoid x receptor
- enterohepatic
- circulation
- ursodeoxycholic acid
- unifying hypothesis
- biliary
- epithelia
- nuclear receptor
- hco3-umbrella
- knockout mice
- diarrhea
- Gastroenterology & Hepatology
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Baghdasaryan, A.
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Fuchs, C. D.
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Osterreicher, C. ...
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Lemberger, U. J.
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Halilbasic, E.
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Pahlman, I.
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show more...
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Graffner, H.
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Krones, E.
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Fickert, P.
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Wahlström, Annik ...
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Ståhlman, Marcus ...
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Paumgartner, G.
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Marschall, Hanns ...
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Trauner, M.
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Gastroenterology ...
- Articles in the publication
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Journal of Hepat ...
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University of Gothenburg