Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis

被引：152

作者：

Baghdasaryan, Anna ^{[1
,2
,3
]}

Fuchs, Claudia D. ^{[1
]}

Oesterreicher, Christoph H. ^{[4
]}

Lemberger, Ursula J. ^{[1
,4
]}

Halilbasic, Emina ^{[1
]}

Pahlman, Ingrid ^{[5
]}

Graffner, Hans ^{[5
]}

Krones, Elisabeth ^{[2
]}

Fickert, Peter ^{[2
]}

Wahlstrom, Annika ^{[6
]}

Stahlman, Marcus ^{[6
]}

Paumgartner, Gustav ^{[1
]}

Marschall, Hanns-Ulrich ^{[6
]}

Trauner, Michael ^{[1
]}

机构：

[1] Med Univ Vienna, Dept Internal Med 3, Div Gastroenterol & Hepatol, Hans Popper Lab Mol Hepatol, A-1090 Vienna, Austria

[2] Med Univ Graz, Dept Internal Med, Div Gastroenterol & Hepatol, Lab Expt & Mol Hepatol, Graz, Austria

[3] Med Univ Graz, Dept Pediat & Adolescent Med, Graz, Austria

[4] Med Univ Vienna, Ctr Physiol & Pharmacol, Inst Pharmacol, Vienna, Austria

[5] Albireo Pharma, Gothenburg, Sweden

[6] Univ Gothenburg, Inst Med, Dept Mol & Clin Med, Sahlgrenska Acad, Gothenburg, Sweden

来源：

JOURNAL OF HEPATOLOGY | 2016年 / 64卷 / 03期

关键词：

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; KNOCKOUT MICE; HCO3-UMBRELLA; DIARRHEA;

D O I：

10.1016/j.jhep.2015.10.024

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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.

引用

页码：674 / 681

页数：8

共 47 条

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