Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis
Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis
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DOI：
10.1016/j.jhep.2015.10.024
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发表时间：
2016-03-01
影响因子：
25.7
通讯作者：
Trauner, Michael
中科院分区：
文献类型：
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作者：
Baghdasaryan, Anna;Fuchs, Claudia D.;Trauner, Michael
背景和目的：大约95%的胆汁酸（BAs）排泄到胆汁中，在肠道中被重新吸收，并循环回肝脏进一步进行胆汁分泌。因此，药物抑制回肠根尖钠依赖性BA转运蛋白（ASBT/SLC10A2）可能对BA介导的胆汁淤积性肝脏和胆管损伤有保护作用。方法：8周龄Mdr2(-/-) （Abcb4(-/-)）小鼠（胆汁淤积性肝损伤和硬化性胆管炎模型）分别饲喂添加A4250 (0.01% w/w)（一种高效选择性ASBT抑制剂）或鼠粮。A4250治疗4周后进行肝损伤生化和组织学评估。通过RT-PCR从肝脏和回肠匀浆中评估BA稳态、炎症和纤维化相关基因的表达谱。通过RNA表达谱和免疫组织化学评估肠道炎症。饲喂ASBT抑制剂1周后，分析其胆汁流量和组成，以及胆汁和粪便BA谱。结果：A4250改善了Mdr2（-/-）小鼠的硬化性胆管炎，显著降低血清丙氨酸转氨酶、碱性磷酸酶和BAs水平，肝脏促炎（tnf - α、Vcam1、Mcp-1）和促纤维化（Col1a1、Col1a2）基因的表达和胆管增殖（细胞角蛋白19 (CK19) mRNA和免疫组化）。此外，A4250显著减少胆汁流量和胆汁BA输出，这与Bsep转录减少有关，而Ntcp和Cyp7a1被诱导。重要的是，A4250显著减少胆道BA分泌，但保留HCO3-和胆道磷脂分泌，导致HCO3-/BA和PL/BA比值增加。此外，A4250在不引起腹泻的情况下显著增加了粪便BA的排泄量，并改变了BA池的组成，导致初级BA牛头- β -苦胆酸和牛头胆酸的浓度降低。结论：药物抑制ASBT可通过降低小鼠胆道BA浓度减轻胆汁淤积肝和胆管损伤。(C) 2015欧洲肝脏研究协会。Elsevier B.V.版权所有。
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.