AHR is a master regulator of diverse pathways in endogenous metabolism.
AHR is a master regulator of diverse pathways in endogenous metabolism.
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DOI：
10.1038/s41598-022-20572-2
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发表时间：
2022-10-05
影响因子：
4.6
通讯作者：
Nigam, Sanjay K.
中科院分区：
文献类型：
--
作者：
Granados, Jeffry C.;Falah, Kian;Koo, Imhoi;Morgan, Ethan W.;Perdew, Gary H.;Patterson, Andrew D.;Jamshidi, Neema;Nigam, Sanjay K.
芳烃受体 (AHR) 是一种转录因子，在解毒、发育、免疫反应、慢性肾病和其他综合征中发挥作用。它在拟议的遥感和信号网络中调节药物转运蛋白和药物代谢酶的表达，通过代谢物和信号分子参与器官间通讯。在这里，我们使用综合组学方法来分析其对从器官到细胞器的多个尺度的代谢的贡献。 Ahr−/− 小鼠的整体代谢组学分析揭示了 AHR 在调节 290 种代谢物中的作用，这些代谢物涉及影响脂肪酸、胆汁酸、肠道微生物组产物、抗氧化剂、胆碱衍生物和尿毒症毒素的许多生化途径。化学信息学分析表明，AHR 在确定代谢物的疏水性以及可能由转运蛋白介导的进出组织的运动中发挥作用。在已知的 AHR 配体中，吲哚丙酸是唯一显着改变的分子，它在人和小鼠细胞中激活 AHR。为了更深入地了解 AHR，我们采用基因组规模代谢重建来整合敲除转录组学和代谢组学数据，这表明 AHR 在调节有机酸和氧化还原状态中的作用。总之，这些结果表明 AHR 在多个器官和跨多个尺度的代谢和信号传导中发挥着核心作用。
The aryl hydrocarbon receptor (AHR) is a transcription factor with roles in detoxification, development, immune response, chronic kidney disease and other syndromes. It regulates the expression of drug transporters and drug metabolizing enzymes in a proposed Remote Sensing and Signaling Network involved in inter-organ communication via metabolites and signaling molecules. Here, we use integrated omics approaches to analyze its contributions to metabolism across multiple scales from the organ to the organelle. Global metabolomics analysis of Ahr−/− mice revealed the role of AHR in the regulation of 290 metabolites involved in many biochemical pathways affecting fatty acids, bile acids, gut microbiome products, antioxidants, choline derivatives, and uremic toxins. Chemoinformatics analysis suggest that AHR plays a role in determining the hydrophobicity of metabolites and perhaps their transporter-mediated movement into and out of tissues. Of known AHR ligands, indolepropionate was the only significantly altered molecule, and it activated AHR in both human and murine cells. To gain a deeper biological understanding of AHR, we employed genome scale metabolic reconstruction to integrate knockout transcriptomics and metabolomics data, which indicated a role for AHR in regulation of organic acids and redox state. Together, the results indicate a central role of AHR in metabolism and signaling between multiple organs and across multiple scales.
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影响因子：
5.8
作者：
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通讯作者：
Schlesner, Matthias
影响因子：
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Coumoul X
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9.2
作者：
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通讯作者：
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