Normalizing HIF-1α Signaling Improves Cellular Glucose Metabolism and Blocks the Pathological Pathways of Hyperglycemic Damage.
Normalizing HIF-1α Signaling Improves Cellular Glucose Metabolism and Blocks the Pathological Pathways of Hyperglycemic Damage.
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DOI：
10.3390/biomedicines9091139
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发表时间：
2021-09-02
期刊：
影响因子：
4.7
通讯作者：
Menini S
中科院分区：
文献类型：
--
作者：
Iacobini C;Vitale M;Pugliese G;Menini S
细胞内过量葡萄糖代谢诱导线粒体功能障碍和糖酵解中间体转移到分支通路，导致细胞损伤和炎症。高血糖导致的线粒体超氧化物的过量产生被认为是这些生化变化的发起者，但越来越多的证据表明，线粒体超氧化物的产生对于糖尿病并发症的发展是必不可少的。本研究验证了缺氧诱导因子(HIF)-1α和相关的生物能量变化（Warburg效应）在糖毒性中起启动作用的假设。通过使用人内皮细胞和巨噬细胞，我们证明了高糖（HG）诱导HIF-1α活性和从氧化代谢到糖酵解及其主要分支的转换。HIF1-α沉默、羰基捕获和抗糖基化剂_ -肌肽和乙草醛酶-1诱导性物反式白藜芦醇逆转hg诱导的生物能量学/生化变化和内皮单核细胞炎症，表明甲基乙二醛（MGO）是HIF1-α诱导的非缺氧刺激。一致地，MGO模拟HG对HIF-1α诱导的作用，并能够诱导从氧化代谢到糖酵解的转换。从机制上讲，甲基乙二醛通过翻译后糖基化抑制脯氨酸4-羟化酶结构域2酶活性，从而导致HIF1-α稳定。这些发现通过确定HIF-1α是糖毒性的重要介质，可被羰基诱捕剂和乙草醛酶-1诱导剂靶向，为糖尿病并发症的发病机制和预防带来了范式转变。
Intracellular metabolism of excess glucose induces mitochondrial dysfunction and diversion of glycolytic intermediates into branch pathways, leading to cell injury and inflammation. Hyperglycemia-driven overproduction of mitochondrial superoxide was thought to be the initiator of these biochemical changes, but accumulating evidence indicates that mitochondrial superoxide generation is dispensable for diabetic complications development. Here we tested the hypothesis that hypoxia inducible factor (HIF)-1α and related bioenergetic changes (Warburg effect) play an initiating role in glucotoxicity. By using human endothelial cells and macrophages, we demonstrate that high glucose (HG) induces HIF-1α activity and a switch from oxidative metabolism to glycolysis and its principal branches. HIF1-α silencing, the carbonyl-trapping and anti-glycating agent ʟ-carnosine, and the glyoxalase-1 inducer trans-resveratrol reversed HG-induced bioenergetics/biochemical changes and endothelial-monocyte cell inflammation, pointing to methylglyoxal (MGO) as the non-hypoxic stimulus for HIF1-α induction. Consistently, MGO mimicked the effects of HG on HIF-1α induction and was able to induce a switch from oxidative metabolism to glycolysis. Mechanistically, methylglyoxal causes HIF1-α stabilization by inhibiting prolyl 4-hydroxylase domain 2 enzyme activity through post-translational glycation. These findings introduce a paradigm shift in the pathogenesis and prevention of diabetic complications by identifying HIF-1α as essential mediator of glucotoxicity, targetable with carbonyl-trapping agents and glyoxalase-1 inducers.
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影响因子：
8.2
作者：
Berner, A. K.;Brouwers, O.;Stitt, A. W.
通讯作者：
Stitt, A. W.
影响因子：
20.1
作者：
Beckman, Joshua A.;Creager, Mark A.
通讯作者：
Creager, Mark A.
DOI：
10.1111/j.1365-2362.2005.01525.x
发表时间：
2005-12-01
影响因子：
5.5
作者：
Eckardt, KU;Kurtz, A
通讯作者：
Kurtz, A
丙酮酸激酶M2激活剂促进四聚体形成并抑制肿瘤发生。
影响因子：
14.8
作者：
Anastasiou, Dimitrios;Yu, Yimin;Israelsen, William J.;Jiang, Jian-Kang;Boxer, Matthew B.;Hong, Bum Soo;Tempel, Wolfram;Dimov, Svetoslav;Shen, Min;Jha, Abhishek;Yang, Hua;Mattaini, Katherine R.;Metallo, Christian M.;Fiske, Brian P.;Courtney, Kevin D.;Malstrom, Scott;Khan, Tahsin M.;Kung, Charles;Skoumbourdis, Amanda P.;Veith, Henrike;Southall, Noel;Walsh, Martin J.;Brimacombe, Kyle R.;Leister, William;Lunt, Sophia Y.;Johnson, Zachary R.;Yen, Katharine E.;Kunii, Kaiko;Davidson, Shawn M.;Christofk, Heather R.;Austin, Christopher P.;Inglese, James;Harris, Marian H.;Asara, John M.;Stephanopoulos, Gregory;Salituro, Francesco G.;Jin, Shengfang;Dang, Lenny;Auld, Douglas S.;Park, Hee-Won;Cantley, Lewis C.;Thomas, Craig J.;Heiden, Matthew G. Vander
通讯作者：
Heiden, Matthew G. Vander
影响因子：
7.7
作者：
Baynes, JW;Thorpe, SR
通讯作者：
Thorpe, SR