Increased sulfation of bile acids in mice and human subjects with sodium taurocholate cotransporting polypeptide deficiency
Increased sulfation of bile acids in mice and human subjects with sodium taurocholate cotransporting polypeptide deficiency
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牛磺胆酸钠共转运多肽缺乏的小鼠和人类受试者中胆汁酸的硫酸化增加。
DOI：
10.1074/jbc.ra118.007179
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发表时间：
2019-08-02
影响因子：
4.8
通讯作者：
Li, Wenhui
中科院分区：
文献类型：
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作者：
Mao, Fengfeng;Liu, Teng;Li, Wenhui
牛磺胆酸钠共转运多肽（NTCP，由SLC 10a 1/SLC 10A 1编码）缺乏可导致小鼠和人的高胆血症，但无明显症状。然而，NTCP缺乏引起的长期高胆血症的后果和反应仍然在很大程度上未被探索。在这里，我们分析了Slc 10a 1（-/-）小鼠血清总胆汁酸（TBA）水平的终身动态，我们还评估了33名SLC 10A 1功能丧失变异体p.Ser267Phe的年轻个体TBA水平的变化。我们发现，在Slc 10a 1（-/-）小鼠和p.Ser267Phe个体中，总体血清TBA水平倾向于随着年龄的增长而逐渐降低。肝脏mRNA表达谱显示高胆血症Slc 10a 1（-/-）小鼠中显著的转录改变，包括胆汁酸（BA）合成的抑制，BA解毒的增强和BA转运的改变。磺基转移酶（SULT）家族的成员在高胆血症Slc 10a 1（-/-）小鼠的肝脏中表现出最显著的增加，并且它们的BA硫酸盐之一，牛磺石胆酸3-硫酸盐显著增加。重要的是，与小鼠研究一致，p.Ser267Phe个体血清中58种BA的综合分析显示BA硫酸盐水平显著增加。总之，我们的研究结果表明，增强的BA硫酸化是Slc 10a 1/SLC 10A 1缺乏的小鼠和人类中BA解毒和消除的主要机制。
Sodium taurocholate cotransporting polypeptide (NTCP, encoded by Slc10a1/SLC10A1) deficiency can result in hypercholanemia but no obvious symptoms in both mice and humans. However, the consequence of and response to long-term hypercholanemia caused by NTCP deficiency remain largely unexplored. Here, we analyzed lifelong dynamics of serum total bile acid (TBA) levels in Slc10a1(-/-) mice, and we also assessed changes of TBA levels in 33 young individuals with SLC10A1 loss-of-function variant p.Ser267Phe. We found that overall serum TBA levels tended to decrease gradually with age in both Slc10a1(-/-) mice and p.Ser267Phe individuals. Liver mRNA profiling revealed notable transcription alterations in hypercholanemic Slc10a1(-/-) mice, including inhibition of bile acid (BA) synthesis, enhancement of BA detoxification, and altered BA transport. Members of the sulfotransferase (SULT) family showed the most dramatic increases in livers of hypercholanemic Slc10a1(-/-) mice, and one of their BA sulfates, taurolithocholic acid 3-sulfate, significantly increased. Importantly, consistent with the mouse studies, comprehensive profiling of 58 BA species in sera of p.Ser267Phe individuals revealed a markedly increased level of BA sulfates. Together, our findings indicate that the enhanced BA sulfation is a major mechanism for BA detoxification and elimination in both mice and humans with Slc10a1/SLC10A1 deficiency.