Our findings position lysosomal cholesterol hydrolysis as a critical process that prevents metabolic inflammation by enabling efficient macrophage apoptotic cell clearance.

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.