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      HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders

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          Abstract

          Elevating HDL levels reduces Glut1 expression, dampens myeloproliferation, and prevents fat loss in multiple mouse models.

          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.

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          Author and article information

          Journal
          J Exp Med
          J. Exp. Med
          jem
          The Journal of Experimental Medicine
          The Rockefeller University Press
          0022-1007
          1540-9538
          11 February 2013
          : 210
          : 2
          : 339-353
          Affiliations
          [1 ]Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110
          [2 ]Department of Medicine, Division of Molecular Medicine, Columbia University, New York, NY 10032
          [3 ]Department of Medical Biochemistry, Academic Medical Center of Amsterdam, University of Amsterdam, 1105 Amsterdam, Netherlands
          [4 ]Human Oncology and Pathogenesis Program; and [5 ]Leukemia Service, Department of Medicine; Memorial Sloan-Kettering Cancer Center, New York, NY 10065
          [6 ]Institute of Clinical Chemistry and Clinical Pharmacology, University Clinic Bonn, 53127 Bonn, Germany
          [7 ]Institut National de la Santé et de la Recherche Médicale U1065, Centre Mediterraneen de Medecine Moleculaire (C3M), Avenir, 06204 Nice, France
          Author notes
          CORRESPONDENCE Laurent Yvan-Charvet: ly2159@ 123456columbia.edu
          Article
          20121357
          10.1084/jem.20121357
          3570097
          23319699
          © 2013 Gautier et al.

          This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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