Mice lacking Mrp3 (Abcc3) have normal bile salt transport, but altered hepatic transport of endogenous glucuronides
Mice lacking Mrp3 (Abcc3) have normal bile salt transport, but altered hepatic transport of endogenous glucuronides
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DOI：
10.1016/j.jhep.2005.07.022
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发表时间：
2006-04-01
影响因子：
25.7
通讯作者：
Borst, P
中科院分区：
文献类型：
--
作者：
Zelcer, N;van de Wetering, K;Borst, P
背景/目的：多药耐药蛋白3 （MRP3）在体外转运胆盐和葡萄糖醛酸盐缀合物，并被认为在胆汁淤积中保护肝脏。在体内，Mrp3的缺失是否会影响这些过程还有待检验。方法：制备Mrp3缺陷小鼠，通过(1)：回肠移植us- chamber(2)、胆管结扎时的肝脏(3)、肝脏灌注实验和(4)体外水泡摄取实验，检测Mrp3对胆盐和葡萄糖醛酸盐缀合物运输的贡献。结果：Mrp3（(-/-)）小鼠无明显表型。在WT和mrp3缺陷小鼠的牛胆酸的经回肠转运中没有发现差异。胆管结扎后，Mrp3（(-/-)）和WT小鼠的组织学肝损伤和血清胆盐水平没有差异，但Mrp3缺陷小鼠的血清胆红素葡萄糖醛酸盐浓度较低。在体外，羟胆酸和羟脱氧胆酸的葡萄糖醛酸缀合物是MRP3的底物，在缺乏MRP3的肝脏中，羟脱氧胆酸灌注后，羟脱氧胆酸-葡萄糖醛酸的正弦分泌减少。结论：Mrp3在胆盐生理中没有主要作用，但参与葡萄糖醛酸化化合物的运输，其中可能包括人体内的葡萄糖醛酸化胆盐。(c) 2005年欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background/Aim: Multidrug Resistance Protein 3 (MRP3) transports bile salts and glucuronide conjugates in vitro and is postulated to protect the liver in cholestasis. Whether the absence of Mrp3 affects these processes in vivo is tested.Methods: Mrp3-deficient mice were generated and the contribution of Mrp3 to bile salt and glucuronide conjugate transport was tested in (1): an Ussing-chamber set-up with ileal explants (2), the liver during bile-duct ligation (3), liver perfusion experiments, and (4) in vitro vesicular uptake experiments.Results: The Mrp3((-/-)) mice show no overt phenotype. No differences between WT and Mrp3-deficient mice were found in the trans-ileal transport of taurocholate. After bile-duct ligation, there were no differences in histological liver damage and serum bile salt levels between Mrp3((-/-)) and WT mice, but Mrp3-deficient mice had lower serum bilirubin glucuronide concentrations. Glucuronide conjugates of hyocholate and hyodeoxycholate are substrates of MRP3 in vitro and in livers that lack Mrp3, there is reduced sinusoidal secretion of hyodeoxycholate-glucuronide after perfusion with hyodeoxycholate.Conclusions: Mrp3 does not have a major role in bile salt physiology, but is involved in the transport of glucuronidated compounds, which could include glucuronidated bile salts in humans. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.