title: Disruption of Glut1 in Hematopoietic Stem Cells Prevents Myelopoiesis and Enhanced Glucose Flux in Atheromatous Plaques of ApoE(-/-) Mice.
abstract: BACKGROUND
  Inflamed atherosclerotic plaques can be visualized by noninvasive positron emission and computed tomographic imaging with (18)F-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.
  
  
  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 1α 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 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.
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France (V.S., M.V., S.I., S.G.-P., R.G., L.Y.-C.); Division of Molecular Medicine, Department of Medicine (M.W.) and Department of Neurology (D.C.D.V.), Columbia University, New York, NY; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Hôpital de la Pitié, Paris, France (E.L.G.); Pierre & Marie Curie University, Université Paris 06, Paris, France (E.L.G.); Institute of Cardiometabolism and Nutrition (ICAN), Boulevard de l'Hôpital, Paris, France (E.L.G.); and Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL (E.B.T.).
authors.forename: Vincent
authors.initials: V
authors.lastname: Sarrazy
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France (V.S., M.V., S.I., S.G.-P., R.G., L.Y.-C.); Division of Molecular Medicine, Department of Medicine (M.W.) and Department of Neurology (D.C.D.V.), Columbia University, New York, NY; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Hôpital de la Pitié, Paris, France (E.L.G.); Pierre & Marie Curie University, Université Paris 06, Paris, France (E.L.G.); Institute of Cardiometabolism and Nutrition (ICAN), Boulevard de l'Hôpital, Paris, France (E.L.G.); and Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL (E.B.T.).
authors.forename: Manon
authors.initials: M
authors.lastname: Viaud
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France (V.S., M.V., S.I., S.G.-P., R.G., L.Y.-C.); Division of Molecular Medicine, Department of Medicine (M.W.) and Department of Neurology (D.C.D.V.), Columbia University, New York, NY; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Hôpital de la Pitié, Paris, France (E.L.G.); Pierre & Marie Curie University, Université Paris 06, Paris, France (E.L.G.); Institute of Cardiometabolism and Nutrition (ICAN), Boulevard de l'Hôpital, Paris, France (E.L.G.); and Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL (E.B.T.).
authors.forename: Marit
authors.initials: M
authors.lastname: Westerterp
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France (V.S., M.V., S.I., S.G.-P., R.G., L.Y.-C.); Division of Molecular Medicine, Department of Medicine (M.W.) and Department of Neurology (D.C.D.V.), Columbia University, New York, NY; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Hôpital de la Pitié, Paris, France (E.L.G.); Pierre & Marie Curie University, Université Paris 06, Paris, France (E.L.G.); Institute of Cardiometabolism and Nutrition (ICAN), Boulevard de l'Hôpital, Paris, France (E.L.G.); and Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL (E.B.T.).
authors.forename: Stoyan
authors.initials: S
authors.lastname: Ivanov
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France (V.S., M.V., S.I., S.G.-P., R.G., L.Y.-C.); Division of Molecular Medicine, Department of Medicine (M.W.) and Department of Neurology (D.C.D.V.), Columbia University, New York, NY; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Hôpital de la Pitié, Paris, France (E.L.G.); Pierre & Marie Curie University, Université Paris 06, Paris, France (E.L.G.); Institute of Cardiometabolism and Nutrition (ICAN), Boulevard de l'Hôpital, Paris, France (E.L.G.); and Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL (E.B.T.).
authors.forename: Sophie
authors.initials: S
authors.lastname: Giorgetti-Peraldi
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France (V.S., M.V., S.I., S.G.-P., R.G., L.Y.-C.); Division of Molecular Medicine, Department of Medicine (M.W.) and Department of Neurology (D.C.D.V.), Columbia University, New York, NY; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Hôpital de la Pitié, Paris, France (E.L.G.); Pierre & Marie Curie University, Université Paris 06, Paris, France (E.L.G.); Institute of Cardiometabolism and Nutrition (ICAN), Boulevard de l'Hôpital, Paris, France (E.L.G.); and Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL (E.B.T.).
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Guinamard
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France (V.S., M.V., S.I., S.G.-P., R.G., L.Y.-C.); Division of Molecular Medicine, Department of Medicine (M.W.) and Department of Neurology (D.C.D.V.), Columbia University, New York, NY; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Hôpital de la Pitié, Paris, France (E.L.G.); Pierre & Marie Curie University, Université Paris 06, Paris, France (E.L.G.); Institute of Cardiometabolism and Nutrition (ICAN), Boulevard de l'Hôpital, Paris, France (E.L.G.); and Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL (E.B.T.).
authors.forename: Emmanuel L
authors.initials: EL
authors.lastname: Gautier
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France (V.S., M.V., S.I., S.G.-P., R.G., L.Y.-C.); Division of Molecular Medicine, Department of Medicine (M.W.) and Department of Neurology (D.C.D.V.), Columbia University, New York, NY; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Hôpital de la Pitié, Paris, France (E.L.G.); Pierre & Marie Curie University, Université Paris 06, Paris, France (E.L.G.); Institute of Cardiometabolism and Nutrition (ICAN), Boulevard de l'Hôpital, Paris, France (E.L.G.); and Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL (E.B.T.).
authors.forename: Edward B
authors.initials: EB
authors.lastname: Thorp
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France (V.S., M.V., S.I., S.G.-P., R.G., L.Y.-C.); Division of Molecular Medicine, Department of Medicine (M.W.) and Department of Neurology (D.C.D.V.), Columbia University, New York, NY; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Hôpital de la Pitié, Paris, France (E.L.G.); Pierre & Marie Curie University, Université Paris 06, Paris, France (E.L.G.); Institute of Cardiometabolism and Nutrition (ICAN), Boulevard de l'Hôpital, Paris, France (E.L.G.); and Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL (E.B.T.).
authors.forename: Darryl C
authors.initials: DC
authors.lastname: De Vivo
authors.affiliation: From the Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France (V.S., M.V., S.I., S.G.-P., R.G., L.Y.-C.); Division of Molecular Medicine, Department of Medicine (M.W.) and Department of Neurology (D.C.D.V.), Columbia University, New York, NY; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1166, Hôpital de la Pitié, Paris, France (E.L.G.); Pierre & Marie Curie University, Université Paris 06, Paris, France (E.L.G.); Institute of Cardiometabolism and Nutrition (ICAN), Boulevard de l'Hôpital, Paris, France (E.L.G.); and Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL (E.B.T.). laurent.yvancharvet@unice.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Yvan-Charvet
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency; D016026:Bone Marrow Transplantation; D002455:Cell Division; D053648:Cytokine Receptor Common beta Subunit / Q000502:physiology; D018450:Disease Progression; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000172:deficiency / Q000502:physiology*; D006019:Glycolysis; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000502:physiology; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039902:Multipotent Stem Cells / Q000378:metabolism; D038042:Myelopoiesis / Q000502:physiology*; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016185:Receptors, Interleukin-3 / Q000037:antagonists & inhibitors / Q000502:physiology; D013154:Spleen / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D053648:Cytokine Receptor Common beta Subunit; D051272:Glucose Transporter Type 1; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D016185:Receptors, Interleukin-3; C495678:Slc2a1 protein, mouse; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D008687:Metformin; D005947:Glucose
keywords: atherosclerosis; bone marrow; cholesterol; glucose transporter type 1; glycolysis; myeloid cells