Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia.
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia.
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DOI：
10.1038/nature10602
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发表时间：
2011-11-20
期刊：
影响因子：
64.8
通讯作者：
Stephanopoulos, Gregory
中科院分区：
文献类型：
--
作者：
Metallo, Christian M.;Gameiro, Paulo A.;Bell, Eric L.;Mattaini, Katherine R.;Yang, Juanjuan;Hiller, Karsten;Jewell, Christopher M.;Johnson, Zachary R.;Irvine, Darrell J.;Guarente, Leonard;Kelleher, Joanne K.;Vander Heiden, Matthew G.;Iliopoulos, Othon;Stephanopoulos, Gregory
乙酰辅酶A（AcCoA）是脂肪酸合成和蛋白质乙酰化的核心生物合成前体。在哺乳动物细胞代谢的传统观点中，AcCoA主要由葡萄糖衍生的丙酮酸通过柠檬酸穿梭和胞质中的三磷酸腺苷柠檬酸裂解酶（ACL）产生。然而，表现出有氧糖酵解的增殖细胞以及暴露于缺氧环境的细胞会将葡萄糖近乎按化学计量水平转化为乳酸，使葡萄糖碳偏离三羧酸循环（TCA）和脂肪酸合成。尽管谷氨酰胺的消耗水平超过氮生物合成所需，但缺氧细胞中谷氨酰胺代谢的调节和利用尚未得到充分理解。在此我们表明，人类细胞利用α - 酮戊二酸（αKG）的还原代谢来合成用于脂质合成的AcCoA。这种依赖异柠檬酸脱氢酶1（IDH1）的途径在正常培养条件下的大多数细胞系中是活跃的，但在缺氧条件下生长的细胞几乎完全依赖谷氨酰胺衍生的αKG的还原羧化来进行从头脂肪生成。此外，缺乏冯·希佩尔 - 林道（VHL）肿瘤抑制蛋白的肾细胞系即使在正常氧水平下也优先利用还原型谷氨酰胺代谢进行脂质生物合成。这些结果确定了氧在调节碳利用以产生AcCoA并支持哺乳动物细胞中脂质合成方面的关键作用。
Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty acid synthesis and protein acetylation. In the conventional view of mammalian cell metabolism, AcCoA is primarily generated from glucose-derived pyruvate through the citrate shuttle and adenosine triphosphate citrate lyase (ACL) in the cytosol. However, proliferating cells that exhibit aerobic glycolysis and those exposed to hypoxia convert glucose to lactate at near stoichiometric levels, directing glucose carbon away from the tricarboxylic acid cycle (TCA) and fatty acid synthesis. Although glutamine is consumed at levels exceeding that required for nitrogen biosynthesis, the regulation and utilization of glutamine metabolism in hypoxic cells is not well understood. Here we show that human cells employ reductive metabolism of alpha-ketoglutarate (αKG) to synthesize AcCoA for lipid synthesis. This isocitrate dehydrogenase 1 (IDH1) dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived αKG for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel-Lindau (VHL) tumor suppressor protein preferentially utilize reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. These results identify a critical role for oxygen in regulating carbon utilization in order to produce AcCoA and support lipid synthesis in mammalian cells.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
9.9
作者：
Gaglio, Daniela;Metallo, Christian M.;Chiaradonna, Ferdinando
通讯作者：
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影响因子：
4.8
作者：
ROSIERS, CD;DIDONATO, L;BRUNENGRABER, H
通讯作者：
BRUNENGRABER, H
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11.2
作者：
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影响因子：
50.3
作者：
Hatzivassiliou, G;Zhao, FP;Thompson, CB
通讯作者：
Thompson, CB