Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE(-/-) Mice

作者：Sarrazy Vincent; Viaud Manon; Westerterp Marit; Ivanov Stoyan; Giorgetti Peraldi Sophie; Guinamard Rodolphe; Gautier Emmanuel L; Thorp Edward B; De Vivo Darryl C; Yvan Charvet Laurent

来源：Circulation Research, 2016, 118(7): 1062-1077.

DOI：10.1161/CIRCRESAHA.115.307599

• glucose transporter type 1
• cholesterol
• myeloid cells
• atherosclerosis
• glycolysis
• bone marrow

Rationale:
Inflamed atherosclerotic plaques can be visualized by noninvasive positron emission and computed tomographic imaging with F-18-fluorodeoxyglucose, a glucose analog, but the underlying mechanisms are poorly understood.
Objective:
Here, we directly investigated the role of Glut1-mediated glucose uptake in apolipoprotein E-deficient (ApoE(-/-)) mouse model of atherosclerosis.
Methods and Results:
We first showed that the enhanced glycolytic flux in atheromatous plaques of ApoE(-/-) mice was associated with the enhanced metabolic activity of hematopoietic stem and multipotential progenitor cells and higher Glut1 expression in these cells. Mechanistically, the regulation of Glut1 in ApoE(-/-) hematopoietic stem and multipotential progenitor cells was not because of alterations in hypoxia-inducible factor 1 alpha signaling or the oxygenation status of the bone marrow but was the consequence of the activation of the common beta subunit of the granulocyte-macrophage colony-stimulating factor/interleukin-3 receptor driving glycolytic substrate utilization by mitochondria. By transplanting bone marrow from WT, Glut1(+/-), ApoE(-/-), and ApoE(-/-)Glut1(+/-) mice into hypercholesterolemic ApoE-deficient mice, we found that Glut1 deficiency reversed ApoE(-/-) hematopoietic stem and multipotential progenitor cell proliferation and expansion, which prevented the myelopoiesis and accelerated atherosclerosis of ApoE(-/-) mice transplanted with ApoE(-/-) bone marrow and resulted in reduced glucose uptake in the spleen and aortic arch of these mice.
Conclusions:
We identified that Glut1 connects the enhanced glucose uptake in atheromatous plaques of ApoE(-/-) mice with their myelopoiesis through regulation of hematopoietic stem and multipotential progenitor cell maintenance and myelomonocytic fate and suggests Glut1 as potential drug target for atherosclerosis.

• 出版日期2016-4-1
• 单位西北大学