The drug transporter OAT3 (SLC22A8) and endogenous metabolite communication via the gut-liver-kidney axis
The drug transporter OAT3 (SLC22A8) and endogenous metabolite communication via the gut-liver-kidney axis
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DOI：
10.1074/jbc.m117.796516
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发表时间：
2017-09-22
影响因子：
4.8
通讯作者：
Nigam, Sanjay K.
中科院分区：
文献类型：
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作者：
Bush, Kevin T.;Wu, Wei;Nigam, Sanjay K.
有机阴离子转运体OAT1 （SLC22A6）和OAT3 （SLC22A8）对药物具有相似的底物特异性，但对于内源性底物是否同样如此尚不清楚。通过LC/MS对Oat3KO （Oat3敲除）中600多种代谢物的分析，我们证明了Oat3参与肠道微生物组产物、关键代谢物和信号分子的运动，包括那些流经肝脏-肾脏轴的分子。受影响的主要途径包括胆汁酸、类黄酮、营养物质、氨基酸（包括尿毒症毒素色氨酸衍生物）和脂质代谢。OAT3在消除肝脏衍生的II期代谢物中也很关键，特别是那些正在进行葡萄糖醛酸化的代谢物。理化特征分析显示9个不同的代谢物群；大多数簇中至少有一个成员先前已在运输分析中得到验证。与药物与OATs相互作用相反，在Oat1KO中积累的内源性代谢物（Oat1敲除）与Oat3KO在物理化学性质上存在明显差异；它们在大小、环数、疏水性和分子复杂性上都有很大的不同。与遥感和信号传导假说一致，这些数据支持OAT转运蛋白通过转运蛋白介导的关键代谢物和信号分子（如肠道微生物组-肠道-血液-肝脏-肾脏-tourine）的运动在器官间和生物体间的远程通信中的重要性。我们讨论了燕麦与代谢物传感和信号通路（如胆汁酸）之间密切联系的可能性。此外，代谢组学和通路分析支持OAT1在肾近端小管代谢中发挥更大作用，而OAT3在全身代谢中相对更重要，调节流经肠、肝和肾的代谢物水平。
The organic anion transporters OAT1 (SLC22A6) and OAT3 (SLC22A8) have similar substrate specificity for drugs, but it is far from clear whether this holds for endogenous substrates. By analysis of more than 600 metabolites in the Oat3KO (Oat3 knockout) by LC/MS, we demonstrateOAT3involvement in the movement of gut microbiome products, key metabolites, and signaling molecules, including those flowing through the gutliver-kidney axis. Major pathways affected included those involved in metabolism of bile acids, flavonoids, nutrients, amino acids (including tryptophan-derivatives that are uremic toxins), and lipids. OAT3 is also critical in elimination of liverderived phase II metabolites, particularly those undergoing glucuronidation. Analysis of physicochemical features revealed nine distinct metabolite groups; at least one member of most clusters has been previously validated in transport assays. In contrast to drugs interacting with the OATs, endogenous metabolites accumulating in the Oat1KO (Oat1 knockout) versus Oat3KO have distinct differences in their physicochemical properties; they are very different in size, number of rings, hydrophobicity, and molecular complexity. Consistent with the Remote Sensing and Signaling Hypothesis, the data support the importance of the OAT transporters in inter-organ and interorganismal remote communication via transporter-mediated movement of key metabolites and signaling molecules (e. g. gut microbiome-to-intestine-to-blood-to-liver-to-kidney-tourine). We discuss the possibility of an intimate connection between OATs and metabolite sensing and signaling pathways (e. g. bile acids). Furthermore, the metabolomics and pathway analysis support the view that OAT1 plays a greater role in kidney proximal tubule metabolism and OAT3 appears relatively more important in systemic metabolism, modulating levels of metabolites flowing through intestine, liver, and kidney.