Circulating metabolite homeostasis achieved through mass action.
Circulating metabolite homeostasis achieved through mass action.
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DOI：
10.1038/s42255-021-00517-1
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发表时间：
2022-01
影响因子：
20.8
通讯作者：
Rabinowitz, Joshua D.
中科院分区：
文献类型：
--
作者：
Li, Xiaoxuan;Hui, Sheng;Mirek, Emily T.;Jonsson, William O.;Anthony, Tracy G.;Lee, Won Dong;Zeng, Xianfeng;Jang, Cholsoon;Rabinowitz, Joshua D.
动态平衡将血清代谢物维持在生理范围内。对于葡萄糖来说，这需要胰岛素，它会抑制葡萄糖的产生，同时加速其消耗。对于其他循环中的代谢物，还没有找到类似的主调节器。在这里，我们表明，在小鼠体内，许多循环代谢物通过三羧酸循环(TCA)循环被清除，其线性比例与它们的循环浓度成正比。静脉注射大量循环代谢产物(必需氨基酸、丝氨酸、丙氨酸、柠檬酸、3-羟基丁酸)，并用同位素标记法测定其流量。扰动注入引起的循环浓度增加几乎不改变生产通量，而线性地增加了消耗通量和TCA的贡献。在饲喂、禁食和高蛋白和低蛋白饲料中，浓度和消耗通量之间的相同质量作用关系基本保持，禁食期间的氨基酸平衡进一步得到内源蛋白质分解代谢增强的支持。因此，尽管哺乳动物有丰富的调节机制，但循环代谢产物的动态平衡基本上是通过大量作用驱动的氧化实现的。
Homeostasis maintains serum metabolites within physiological ranges. For glucose, this requires insulin, which suppresses glucose production while accelerating its consumption. For other circulating metabolites, a comparable master regulator has yet to be discovered. Here we show that, in mice, many circulating metabolites are cleared via the tricarboxylic acid cycle (TCA) cycle in linear proportionality to their circulating concentration. Abundant circulating metabolites (essential amino acids, serine, alanine, citrate, 3-hydroxybutyrate) were administered intravenously in perturbative amounts and their fluxes were measured using isotope labelling. The increased circulating concentrations induced by the perturbative infusions hardly altered production fluxes while linearly enhancing consumption fluxes and TCA contributions. The same mass action relationship between concentration and consumption flux largely held across feeding, fasting and high- and low-protein diets, with amino acid homeostasis during fasting further supported by enhanced endogenous protein catabolism. Thus, despite the copious regulatory machinery in mammals, circulating metabolite homeostasis is achieved substantially through mass action-driven oxidation.
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