A Network of SLC and ABC Transporter and DME Genes Involved in Remote Sensing and Signaling in the Gut-Liver-Kidney Axis
A Network of SLC and ABC Transporter and DME Genes Involved in Remote Sensing and Signaling in the Gut-Liver-Kidney Axis
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DOI：
10.1038/s41598-019-47798-x
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发表时间：
2019-08-15
影响因子：
4.6
通讯作者：
Nigam, Sanjay K.
中科院分区：
文献类型：
--
作者：
Rosenthal, Sara Brin;Bush, Kevin T.;Nigam, Sanjay K.
对药物吸收、分布、代谢和消除（ADME）起中心作用的基因也调节许多内源性分子。遥感和信号假说认为，ADME基因为中心的网络，包括SLC和ABC的“药物”转运蛋白，“药物”代谢酶（DME），和调节基因是必不可少的器官间通信通过代谢产物，信号分子，抗氧化剂，肠道微生物组产品，尿毒症溶质，尿毒症毒素。通过跨组织共表达网络分析，肠道、肝脏和肾脏（GLK）形成了SLC转运蛋白、ABC转运蛋白和DME的高度连接的组织特异性簇。SLC 22、SLC 25和SLC 35家族是网络中心，器官间和器官内的连接比其他家族多。对GLK网络的分析揭示了关键的生理途径（例如，包括胆汁酸和尿酸）。对与网络相互作用的其他基因的搜索确定了HNF 4 α，HNF 1 α和PXR。敲除基因表达数据证实与这些转录因子对ADME基因调控的预测的60-70%相似。利用GLK网络和已知的ADME基因，我们建立了一个试验性的肠-肝-肾“遥感和信号网络”，包括SLC和ABC转运蛋白，以及DME和调节蛋白。连同蛋白质-蛋白质相互作用以优先考虑可能的功能连接，该网络表明多特异性如何与寡特异性和单特异性结合以调节许多内源性小分子的稳态。
Genes central to drug absorption, distribution, metabolism and elimination (ADME) also regulate numerous endogenous molecules. The Remote Sensing and Signaling Hypothesis argues that an ADME gene-centered network-including SLC and ABC "drug" transporters, "drug" metabolizing enzymes (DMEs), and regulatory genes-is essential for inter-organ communication via metabolites, signaling molecules, antioxidants, gut microbiome products, uremic solutes, and uremic toxins. By cross-tissue co-expression network analysis, the gut, liver, and kidney (GLK) formed highly connected tissue-specific clusters of SLC transporters, ABC transporters, and DMEs. SLC22, SLC25 and SLC35 families were network hubs, having more inter-organ and intra-organ connections than other families. Analysis of the GLK network revealed key physiological pathways (e.g., involving bile acids and uric acid). A search for additional genes interacting with the network identified HNF4 alpha, HNF1 alpha, and PXR. Knockout gene expression data confirmed similar to 60-70% of predictions of ADME gene regulation by these transcription factors. Using the GLK network and known ADME genes, we built a tentative gut-liver-kidney "remote sensing and signaling network" consisting of SLC and ABC transporters, as well as DMEs and regulatory proteins. Together with protein-protein interactions to prioritize likely functional connections, this network suggests how multi-specificity combines with oligo-specificity and mono-specificity to regulate homeostasis of numerous endogenous small molecules.