Hypoxia promotes glycogen accumulation through hypoxia inducible factor (HIF)-mediated induction of glycogen synthase 1.
Hypoxia promotes glycogen accumulation through hypoxia inducible factor (HIF)-mediated induction of glycogen synthase 1.
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DOI：
10.1371/journal.pone.0009644
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发表时间：
2010-03-12
期刊：
影响因子：
3.7
通讯作者：
del Peso L
中科院分区：
文献类型：
--
作者：
Pescador N;Villar D;Cifuentes D;Garcia-Rocha M;Ortiz-Barahona A;Vazquez S;Ordoñez A;Cuevas Y;Saez-Morales D;Garcia-Bermejo ML;Landazuri MO;Guinovart J;del Peso L
当氧气变得有限时，细胞通过葡萄糖的厌氧发酵减少线粒体呼吸并增加ATP的产生。低氧诱导因子（HIF）通过调节葡萄糖代谢关键酶的转录在这种代谢转变中起关键作用。在这里，我们表明，氧调节肌肉糖原合成酶（GYS 1）的表达。低氧GYS 1诱导需要HIF活性和其启动子内的低氧反应元件。GYS 1基因诱导与暴露于缺氧的细胞中糖原合成酶活性和糖原积累的显着增加相关。重要的是，HIF 1 α或GYS 1的敲低减弱了缺氧诱导的糖原积累，而GYS 1的过表达足以模拟这种作用。总之，这些结果表明，GYS 1调节HIF在糖原的缺氧积累中起着重要作用。重要的是，我们发现缺氧也上调UTP的表达：葡萄糖-1-磷酸尿苷酰转移酶（UGP 2）和1，4-α葡聚糖分支酶（GBE 1），这两种酶参与糖原的生物合成。因此，缺氧以协调的方式调节几乎所有参与糖原代谢的酶，导致其积累。最后，我们证明，废除糖原合成，敲低GYS 1的表达，损害缺氧预处理，这表明慢性缺氧过程中积累的糖原的生理作用。总之，我们的研究结果揭示了缺氧对葡萄糖代谢的新影响，进一步支持了代谢重编程在细胞适应缺氧中的重要性。
When oxygen becomes limiting, cells reduce mitochondrial respiration and increase ATP production through anaerobic fermentation of glucose. The Hypoxia Inducible Factors (HIFs) play a key role in this metabolic shift by regulating the transcription of key enzymes of glucose metabolism. Here we show that oxygen regulates the expression of the muscle glycogen synthase (GYS1). Hypoxic GYS1 induction requires HIF activity and a Hypoxia Response Element within its promoter. GYS1 gene induction correlated with a significant increase in glycogen synthase activity and glycogen accumulation in cells exposed to hypoxia. Significantly, knockdown of either HIF1α or GYS1 attenuated hypoxia-induced glycogen accumulation, while GYS1 overexpression was sufficient to mimic this effect. Altogether, these results indicate that GYS1 regulation by HIF plays a central role in the hypoxic accumulation of glycogen. Importantly, we found that hypoxia also upregulates the expression of UTP:glucose-1-phosphate urydylyltransferase (UGP2) and 1,4-α glucan branching enzyme (GBE1), two enzymes involved in the biosynthesis of glycogen. Therefore, hypoxia regulates almost all the enzymes involved in glycogen metabolism in a coordinated fashion, leading to its accumulation. Finally, we demonstrated that abrogation of glycogen synthesis, by knock-down of GYS1 expression, impairs hypoxic preconditioning, suggesting a physiological role for the glycogen accumulated during chronic hypoxia. In summary, our results uncover a novel effect of hypoxia on glucose metabolism, further supporting the central importance of metabolic reprogramming in the cellular adaptation to hypoxia.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
DOI：
10.1073/pnas.192342099
发表时间：
2002-10-15
影响因子：
11.1
作者：
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通讯作者：
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作者：
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Ratcliffe, PJ
影响因子：
4.8
作者：
Ros, Susana;Garcia-Rocha, Mar;Guinovart, Joan J.
通讯作者：
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