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

Abstract

Rationale: Inflamed atherosclerotic plaques can be visualized by non-invasive PET-CT imaging with ¹⁸FDG, a glucose analog but the underlying mechanisms are poorly understood.

Objective: Here, we directly investigated the role of Glut1-mediated glucose uptake in ApoE^-/- mouse model of atherosclerosis.

Methods and Results: 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.

Conclusions: 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.