Abstract
A high metabolic rate in myeloproliferative disorders is a common complication of neoplasms, but the underlying mechanisms are incompletely understood. Using three different mouse models of myeloproliferative disorders, including mice with defective cholesterol efflux pathways and two models based on expression of human leukemia disease alleles, we uncovered a mechanism by which proliferating and inflammatory myeloid cells take up and oxidize glucose during the feeding period, contributing to energy dissipation and subsequent loss of adipose mass. In vivo, lentiviral inhibition of Glut1 by shRNA prevented myeloproliferation and adipose tissue loss in mice with defective cholesterol efflux pathway in leukocytes. Thus, Glut1 was necessary to sustain proliferation and potentially divert glucose from fat storage. We also showed that overexpression of the human ApoA-I transgene to raise high-density lipoprotein (HDL) levels decreased Glut1 expression, dampened myeloproliferation, and prevented fat loss. These experiments suggest that inhibition of Glut-1 and HDL cholesterol-raising therapies could provide novel therapeutic approaches to treat the energy imbalance observed in myeloproliferative disorders.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter 1
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ATP Binding Cassette Transporter, Subfamily G, Member 1
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ATP-Binding Cassette Transporters / deficiency
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ATP-Binding Cassette Transporters / genetics
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Adipose Tissue / metabolism
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Adipose Tissue / pathology
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Animals
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Apolipoprotein A-I / genetics
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Bone Marrow Transplantation
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Disease Models, Animal
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Glucose / metabolism
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Glucose Transporter Type 1 / antagonists & inhibitors*
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Glucose Transporter Type 1 / genetics
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Glycolysis
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Humans
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Insulin Resistance
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Interleukin-3 / metabolism
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Leukocytes / metabolism
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Leukocytes / pathology
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Lipoproteins / deficiency
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Lipoproteins / genetics
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Lipoproteins, HDL / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Inbred DBA
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Mice, Knockout
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Mice, Transgenic
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Myeloproliferative Disorders / genetics
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Myeloproliferative Disorders / metabolism*
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Myeloproliferative Disorders / pathology
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Myeloproliferative Disorders / therapy
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Oxidative Phosphorylation
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RNA, Small Interfering / genetics
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Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
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Signal Transduction
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Toll-Like Receptor 4 / metabolism
Substances
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ABCG1 protein, mouse
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ATP Binding Cassette Transporter 1
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ATP Binding Cassette Transporter, Subfamily G, Member 1
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ATP-Binding Cassette Transporters
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Apolipoprotein A-I
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Glucose Transporter Type 1
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Interleukin-3
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Lipoproteins
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Lipoproteins, HDL
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RNA, Small Interfering
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Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
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Slc2a1 protein, mouse
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Tlr4 protein, mouse
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Toll-Like Receptor 4
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Glucose