抑制肠道胆汁酸吸收可改善硬化性胆管炎小鼠模型的胆汁淤积性肝和胆管损伤。
Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis.
机构信息
Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria; Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.
Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
出版信息
J Hepatol. 2016 Mar;64(3):674-81. doi: 10.1016/j.jhep.2015.10.024. Epub 2015 Oct 31.
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 4weeks 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 1week 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 pro-inflammatory (Tnf-α, 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-β-muricholic acid and taurocholic acid.
CONCLUSIONS
Pharmacological ASBT inhibition attenuates cholestatic liver and bile duct injury by reducing biliary BA concentrations in mice.
背景与目的
约 95%的胆汁酸（BAs）排入胆汁后在肠道中被重吸收，并循环回肝脏以进一步进行胆汁分泌。因此，药理学抑制回肠顶端钠依赖性 BA 转运体（ASBT/SLC10A2）可能有助于防止 BA 介导的胆汁淤积性肝和胆管损伤。
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）接受添加 A4250（0.01%w/w）的饮食补充-一种高度有效和选择性的 ASBT 抑制剂-或标准饮食。A4250 治疗 4 周后，通过生化和组织学评估肝损伤。通过 RT-PCR 从肝和回肠匀浆中评估参与 BA 稳态、炎症和纤维化的基因表达谱。通过 RNA 表达谱和免疫组织化学评估肠道炎症。在 ASBT 抑制剂喂养 1 周后分析胆汁流量和成分以及胆汁和粪便 BA 谱。
结果
A4250 改善了 Mdr2(-/-)小鼠的硬化性胆管炎，并显著降低了血清丙氨酸氨基转移酶、碱性磷酸酶和 BAs 水平、肝脏表达的促炎（TNF-α、VCAM1、MCP-1）和促纤维化（COL1A1、COL1A2）基因以及胆管增殖（信使 RNA 和免疫组织化学检测细胞角蛋白 19（CK19））。此外，A4250 显著降低了胆汁流量和胆汁 BA 输出，这与 BSEP 转录减少相关，而 Ntcp 和 Cyp7a1 被诱导。重要的是，A4250 显著减少了胆汁 BA 的分泌，但保留了 HCO3(-)和胆汁磷脂的分泌，导致 HCO3(-)/BA 和 PL/BA 比值增加。此外，A4250 显著增加了粪便 BA 的排泄，而不会引起腹泻和改变 BA 池组成，导致初级 BA 牛磺-β-熊去氧胆酸和牛磺胆酸的浓度降低。
结论
药理学 ASBT 抑制通过降低小鼠胆汁中的 BA 浓度来减轻胆汁淤积性肝和胆管损伤。
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