mEH、NTCP 和 OATP 在肝钠依赖性胆汁酸转运中的作用,Hepatology

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mEH、NTCP 和 OATP 在肝钠依赖性胆汁酸转运中的作用
Hepatology ( IF 12.9 ) Pub Date : 2018-01-30 , DOI: 10.1002/hep.29712
Daniel Levy ₁

Affiliation

mEH、NTCP 和 OATP 在肝钠依赖性胆汁酸转运中的作用。致编辑：最近的研究 (1) 在 Hepatology 中报道，关于使用缺乏 Slco1a/1b 亚型的 OATP 敲除小鼠对结合胆汁酸的肝脏摄取表明 OATP 和 NTCP 是必需的，因为只有 32% 的 NTCP 敲除小鼠表现出血清升高胆汁酸水平 [参考 (1) 中的 8]。然而，该报告并未确定 NTCP 和 OATP 是所有系统中的主要胆汁酸转运蛋白，也未参考下述证明存在替代途径的研究。许多研究已经证实微粒体环氧化物水解酶 (mEH) 在共轭胆汁酸的肝脏转运中发挥着重要作用，包括鉴定出人类 mEH 基因 (EPHX1) 中的两个杂合突变，导致 mEH 表达降低 95% (2) . 后一项研究中的患者在没有肝损伤的情况下表现出血清胆汁酸增加 100 倍，表明运输缺陷，而 NTCP mRNA 和蛋白质表达水平正常。此外，我们最近报道了 (3) 先前在 (2) 中描述的相同 EPHX1 内含子-1 杂合多态性在兰开斯特县旧秩序阿米什人口中的高比例存在，这些人群呈现出许多没有肝损伤的高胆汁性受试者，这表明运输能力。在该人群的 NTCP 基因中未检测到突变。相比之下，在 mEH 水平正常的 fch/fch 小鼠中检测不到 NTCP 和 OATP-1，其中在肝脏中快速检测到高比例的静脉内施用的牛磺胆酸盐[参考文献。42 英寸 (3)]。在用环丙贝特治疗的小鼠中观察到类似的结果，其中 NTCP、OATP-1 和 BSEP 大大降低或检测不到，而血清胆汁酸浓度和胆汁酸分泌率不受影响 [参考文献。43 (3)]。此外，胆汁酸的个体基因表达存在显着差异。42 英寸 (3)]。在用环丙贝特治疗的小鼠中观察到类似的结果，其中 NTCP、OATP-1 和 BSEP 大大降低或检测不到，而血清胆汁酸浓度和胆汁酸分泌率不受影响 [参考文献。43 (3)]。此外，胆汁酸的个体基因表达存在显着差异。42 英寸 (3)]。在用环丙贝特治疗的小鼠中观察到类似的结果，其中 NTCP、OATP-1 和 BSEP 大大降低或检测不到，而血清胆汁酸浓度和胆汁酸分泌率不受影响 [参考文献。43 (3)]。此外，胆汁酸的个体基因表达存在显着差异。

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The role of mEH, NTCP and OATP in hepatic sodium-dependent bile acid transport

The role of mEH, NTCP and OATP in hepatic sodium-dependent bile acid transport. TO THE EDITOR: Recent studies (1) reported in Hepatology concerning the hepatic uptake of conjugated bile acids using OATP knockout mice lacking Slco1a/1b isoforms demonstrate that OATP as well as NTCP are required since only 32% of the NTCP knockout mice exhibited elevated serum bile acid levels [ref 8 in (1)]. This report, however, does not establish that NTCP and OATP are the major bile acid transporters in all systems and do not reference studies described below that demonstrate the existence of alternate pathways. Numerous studies have established that microsomal epoxide hydrolase (mEH) plays a significant role in the hepatic transport of conjugated bile acids including the identification of two heterozygous mutations in the human mEH gene (EPHX1) resulting in a 95% decrease in mEH expression (2). The patient in this latter study exhibited a 100-fold increase in serum bile acids in the absence of liver damage suggesting a defect in transport while NTCP mRNA and protein expression levels were normal. In addition, we recently reported (3) the presence of the same EPHX1 intron-1 heterozygous polymorphism previously described in (2) in a high percentage of the Lancaster County Old Order Amish population that present numerous hypercholanemic subjects without liver injury suggesting the loss of transport capacity. No mutations have been detected in the NTCP gene from this population. In contrast, NTCP and OATP-1 were undetectable in the fch/fch mouse which exhibits normal levels of mEH, where a high percentage of intravenously administered taurocholate was rapidly detected in the liver [ref. 42 in (3)]. Similar results were observed in mice treated with ciprofibrate where NTCP, OATP-1 and BSEP were greatly reduced or undetectable while serum bile acid concentrations and biliary bile acid secretion rates were unaffected [ref. 43 in (3)]. In addition, there is a significant discordance between the ontogenic expression of bile acid

更新日期：2018-01-30

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