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首页> 美国卫生研究院文献>Wiley-Blackwell Online Open >Hepatic uptake of conjugated bile acids is mediated by both sodium taurocholate cotransporting polypeptide and organic anion transporting polypeptides and modulated by intestinal sensing of plasma bile acid levels in mice
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Hepatic uptake of conjugated bile acids is mediated by both sodium taurocholate cotransporting polypeptide and organic anion transporting polypeptides and modulated by intestinal sensing of plasma bile acid levels in mice

机译：牛磺胆酸钠共转运多肽和有机阴离子转运多肽介导肝脏对共轭胆汁酸的摄取并通过肠内检测小鼠血浆胆汁酸水平来调节

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The Na+‐taurocholate cotransporting polypeptide (NTCP/SLC10A1) is believed to be pivotal for hepatic uptake of conjugated bile acids. However, plasma bile acid levels are normal in a subset of NTCP knockout mice and in mice treated with myrcludex B, a specific NTCP inhibitor. Here, we elucidated which transport proteins mediate the hepatic uptake of conjugated bile acids and demonstrated intestinal sensing of elevated bile acid levels in plasma in mice. Mice or healthy volunteers were treated with myrcludex B. Hepatic bile acid uptake kinetics were determined in wild‐type (WT), organic anion transporting polypeptide (OATP) knockout mice (lacking Slco1a/1b isoforms), and human OATP1B1‐transgenic mice. Effects of fibroblast growth factor 19 (FGF19) on hepatic transporter mRNA levels were assessed in rat hepatoma cells and in mice by peptide injection or adeno‐associated virus–mediated overexpression. NTCP inhibition using myrcludex B had only moderate effects on bile acid kinetics in WT mice, but completely inhibited active transport of conjugated bile acid species in OATP knockout mice. Cholesterol 7α‐hydroxylase Cyp7a1 expression was strongly down‐regulated upon prolonged inhibition of hepatic uptake of conjugated bile acids. Fgf15 (mouse counterpart of FGF19) expression was induced in hypercholanemic OATP and NTCP knockout mice, as well as in myrcludex B–treated cholestatic mice, whereas plasma FGF19 was not induced in humans treated with myrcludex B. Fgf15/FGF19 expression was induced in polarized human enterocyte‐models and mouse organoids by basolateral incubation with a high concentration (1 mM) of conjugated bile acids. Conclusion: NTCP and OATPs contribute to hepatic uptake of conjugated bile acids in mice, whereas the predominant uptake in humans is NTCP mediated. Enterocytes sense highly elevated levels of (conjugated) bile acids in the systemic circulation to induce FGF15/19, which modulates hepatic bile acid synthesis and uptake. (Hepatology 2017;66:1631–1643).
机译：Na + -taurocholate共转运多肽（NTCP / SLC10A1）被认为对于肝脏摄取共轭胆汁酸至关重要。但是，血浆胆汁酸水平在一部分NTCP敲除小鼠中以及在用myrcludex B（一种特殊的NTCP抑制剂）治疗的小鼠中是正常的。在这里，我们阐明了哪些转运蛋白介导了肝脏对共轭胆汁酸的摄取，并证明了肠道中小鼠血浆胆汁酸水平升高的感觉。小鼠或健康志愿者接受了Myrcludex B治疗。在野生型（WT），有机阴离子转运多肽（OATP）敲除小鼠（缺少Slco1a / 1b亚型）和人OATP1B1转基因小鼠中测定了肝胆酸摄取动力学。通过肽注射或腺相关病毒介导的过表达，评估了大鼠肝癌细胞和小鼠中成纤维细胞生长因子19（FGF19）对肝转运蛋白mRNA水平的影响。使用myrcludex B的NTCP抑制仅对WT小鼠的胆汁酸动力学有中等程度的影响，但在OATP基因敲除小鼠中完全抑制了结合胆汁酸物质的主动转运。胆固醇对肝胆碱摄取的抑制作用延长，胆固醇7α-羟化酶Cyp7a1的表达明显下调。在高胆固醇血症的OATP和NTCP敲除小鼠以及经myrcludex B治疗的胆汁淤积小鼠中，诱导了Fgf15（与FGF19对应的小鼠）的表达，而在经myrcludex B治疗的人中未诱导血浆FGF19。在极化的条件下诱导了Fgf15 / FGF19的表达。通过高浓度（1 mM）共轭胆汁酸的基底外侧孵育培养人肠上皮细胞模型和小鼠类器官。结论：NTCP和OATPs有助于小鼠肝脏对共轭胆汁酸的摄取，而人类的主要摄取是NTCP介导的。肠上皮细胞在体循环中感觉到（结合的）胆汁酸水平升高，从而诱导FGF15 / 19，从而调节肝胆汁酸的合成和摄取。 （肝脏病学，2017年； 66：1631-1643）。

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