Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE(-/-) Mice.
Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE(-/-) Mice.
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DOI：
10.1161/circresaha.115.307599
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发表时间：
2016-04-01
影响因子：
20.1
通讯作者：
Yvan-Charvet L
中科院分区：
文献类型：
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作者：
Sarrazy V;Viaud M;Westerterp M;Ivanov S;Giorgetti-Peraldi S;Guinamard R;Gautier EL;Thorp EB;De Vivo DC;Yvan-Charvet L
发炎的动脉粥样硬化斑块可以通过使用 18FDG（一种葡萄糖类似物）进行非侵入性 PET-CT 成像来可视化，但其潜在机制尚不清楚。在这里，我们直接研究了 Glut1 介导的葡萄糖摄取在 ApoE−/− 小鼠动脉粥样硬化模型中的作用。我们首先表明，ApoE−/− 小鼠动脉粥样斑块中糖酵解通量的增强与造血干细胞和多能祖细胞 (HSPC) 的代谢活性增强以及这些细胞中较高的 Glut1 表达有关。从机制上讲，ApoE−/− HSPC 中 Glut1 的调节并非由于缺氧诱导因子 1α (HIF1α) 信号传导或骨髓氧合状态的改变所致，而是粒细胞巨噬细胞集落刺激因子/白细胞介素 3 受体的常见 β 亚基激活驱动糖酵解底物利用的结果 通过线粒体。通过将 WT、Glut1+/-、ApoE−/− 和 ApoE−/−Glut1+/- 小鼠的骨髓移植到高胆固醇 ApoE 缺陷小鼠中，我们发现 Glut1 缺陷逆转了 ApoE−/− HSPC 的增殖和扩张，从而阻止了移植 ApoE−/− 小鼠的骨髓生成并加速了动脉粥样硬化。 ApoE−/− BM 导致这些小鼠的脾脏和主动脉弓的葡萄糖摄取减少。我们发现 Glut1 通过调节 HSPC 维持和骨髓单核细胞命运，将 ApoE−/− 小鼠动脉粥样斑块中葡萄糖摄取的增强与其骨髓生成联系起来，并建议 Glut1 作为动脉粥样硬化的潜在药物靶点。
Inflamed atherosclerotic plaques can be visualized by non-invasive PET-CT imaging with 18FDG, a glucose analog but the underlying mechanisms are poorly understood. Here, we directly investigated the role of Glut1-mediated glucose uptake in ApoE−/− mouse model of atherosclerosis. We first show that the enhanced glycolytic flux in atheromatous plaques of ApoE−/− mice was associated with the enhanced metabolic activity of hematopoietic stem and multi-potential progenitors (HSPCs) and higher Glut1 expression in these cells. Mechanistically, the regulation of Glut1 in ApoE−/− HSPCs was not due to alterations in hypoxia-inducible factor 1α (HIF1α) signaling or the oxygenation status of the bone marrow but was the consequence of the activation of the common β subunit of the granulocyte macrophage colony-stimulating factor/interleukin-3 receptor driving glycolytic substrate utilization by mitochondria. By transplanting BM from WT, Glut1+/−, ApoE−/− and ApoE−/−Glut1+/− mice into hypercholesterolemic ApoE deficient mice, we found that Glut1 deficiency reversed ApoE−/− HSPC proliferation and expansion, which prevented the myelopoiesis and accelerated atherosclerosis of ApoE−/− mice transplanted with ApoE−/− BM and resulted in reduced glucose uptake in the spleen and aortic arch of these mice. We identified that Glut1 connects the enhanced glucose uptake in atheromatous plaques of ApoE−/− mice with their myelopoiesis through regulation of HSPC maintenance and myelomonocytic fate and suggest Glut1 as potential drug target for atherosclerosis.