Glucose feeds the TCA cycle via circulating lactate.
Glucose feeds the TCA cycle via circulating lactate.
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DOI：
10.1038/nature24057
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发表时间：
2017-11-02
期刊：
影响因子：
64.8
通讯作者：
Rabinowitz JD
中科院分区：
文献类型：
--
作者：
Hui S;Ghergurovich JM;Morscher RJ;Jang C;Teng X;Lu W;Esparza LA;Reya T;Le Zhan;Yanxiang Guo J;White E;Rabinowitz JD
哺乳动物组织由循环营养物质提供能量，包括葡萄糖、氨基酸和各种中间代谢物。在有氧条件下，葡萄糖通常被认为是由组织通过三羧酸循环(TCA循环)完全燃烧成二氧化碳。或者，葡萄糖可以通过糖酵解分解为乳酸，乳酸本身也是组织和肿瘤的潜在营养物质。循环中的乳酸或其他代谢中间体作为燃料的数量相关性仍不清楚。在这里，我们系统地研究了小鼠体内循环代谢物的流量，发现乳酸可能是TCA循环的主要碳源，从而也是能量的来源。静脉输注13C标记的营养素表明，按摩尔计算，乳酸的循环周转流量是所有代谢物中最高的，在喂食小鼠中是葡萄糖的1.1倍，在禁食小鼠中是葡萄糖的2.5倍；乳酸主要来自葡萄糖，但也来自其他来源。在喂食和禁食的小鼠中，13C-乳酸广泛地标记了所有组织中的TCA循环中间体。定量分析表明，在禁食状态下，除脑组织外，所有组织中葡萄糖对组织TCA代谢的贡献主要是间接的(通过循环乳酸)。在禁食小鼠的基因工程肺癌和胰腺癌肿瘤中，循环中的乳酸对TCA循环中间体的贡献超过了葡萄糖，其中谷氨酰胺在胰腺癌中的贡献大于乳酸。因此，糖酵解和TCA循环在乳酸水平上是解偶联的，乳酸是大多数组织和肿瘤中主要的循环TCA底物。
Mammalian tissues are fuelled by circulating nutrients, including glucose, amino acids, and various intermediary metabolites. Under aerobic conditions, glucose is generally assumed to be burned fully by tissues via the tricarboxylic acid cycle (TCA cycle) to carbon dioxide. Alternatively, glucose can be catabolized anaerobically via glycolysis to lactate, which is itself also a potential nutrient for tissues and tumours. The quantitative relevance of circulating lactate or other metabolic intermediates as fuels remains unclear. Here we systematically examine the fluxes of circulating metabolites in mice, and find that lactate can be a primary source of carbon for the TCA cycle and thus of energy. Intravenous infusions of 13C-labelled nutrients reveal that, on a molar basis, the circulatory turnover flux of lactate is the highest of all metabolites and exceeds that of glucose by 1.1-fold in fed mice and 2.5-fold in fasting mice; lactate is made primarily from glucose but also from other sources. In both fed and fasted mice, 13C-lactate extensively labels TCA cycle intermediates in all tissues. Quantitative analysis reveals that during the fasted state, the contribution of glucose to tissue TCA metabolism is primarily indirect (via circulating lactate) in all tissues except the brain. In genetically engineered lung and pancreatic cancer tumours in fasted mice, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose, with glutamine making a larger contribution than lactate in pancreatic cancer. Thus, glycolysis and the TCA cycle are uncoupled at the level of lactate, which is a primary circulating TCA substrate in most tissues and tumours.
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