title: HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders.
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.
authors: Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.
authors: Emmanuel L
authors: EL
authors: Gautier
authors: Marit
authors: M
authors: Westerterp
authors: Neha
authors: N
authors: Bhagwat
authors: Serge
authors: S
authors: Cremers
authors: Alan
authors: A
authors: Shih
authors: Omar
authors: O
authors: Abdel-Wahab
authors: Dieter
authors: D
authors: Lütjohann
authors: Gwendalyn J
authors: GJ
authors: Randolph
authors: Ross L
authors: RL
authors: Levine
authors: Alan R
authors: AR
authors: Tall
authors: Laurent
authors: L
authors: Yvan-Charvet
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D006019:Glycolysis; D006801:Humans; D007333:Insulin Resistance; D007377:Interleukin-3 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D008074:Lipoproteins / Q000172:deficiency / Q000235:genetics; D008075:Lipoproteins, HDL / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D010085:Oxidative Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D051272:Glucose Transporter Type 1; D007377:Interleukin-3; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D034741:RNA, Small Interfering; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; C495678:Slc2a1 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D005947:Glucose