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

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 o...

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Autores principales: Gautier, Emmanuel L., Westerterp, Marit, Bhagwat, Neha, Cremers, Serge, Shih, Alan, Abdel-Wahab, Omar, Lütjohann, Dieter, Randolph, Gwendalyn J., Levine, Ross L., Tall, Alan R., Yvan-Charvet, Laurent
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570097/
https://www.ncbi.nlm.nih.gov/pubmed/23319699
http://dx.doi.org/10.1084/jem.20121357
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author Gautier, Emmanuel L.
Westerterp, Marit
Bhagwat, Neha
Cremers, Serge
Shih, Alan
Abdel-Wahab, Omar
Lütjohann, Dieter
Randolph, Gwendalyn J.
Levine, Ross L.
Tall, Alan R.
Yvan-Charvet, Laurent
author_facet Gautier, Emmanuel L.
Westerterp, Marit
Bhagwat, Neha
Cremers, Serge
Shih, Alan
Abdel-Wahab, Omar
Lütjohann, Dieter
Randolph, Gwendalyn J.
Levine, Ross L.
Tall, Alan R.
Yvan-Charvet, Laurent
author_sort Gautier, Emmanuel L.
collection PubMed
description 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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spelling pubmed-35700972013-08-11 HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders Gautier, Emmanuel L. Westerterp, Marit Bhagwat, Neha Cremers, Serge Shih, Alan Abdel-Wahab, Omar Lütjohann, Dieter Randolph, Gwendalyn J. Levine, Ross L. Tall, Alan R. Yvan-Charvet, Laurent J Exp Med Article 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. The Rockefeller University Press 2013-02-11 /pmc/articles/PMC3570097/ /pubmed/23319699 http://dx.doi.org/10.1084/jem.20121357 Text en © 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/).
spellingShingle Article
Gautier, Emmanuel L.
Westerterp, Marit
Bhagwat, Neha
Cremers, Serge
Shih, Alan
Abdel-Wahab, Omar
Lütjohann, Dieter
Randolph, Gwendalyn J.
Levine, Ross L.
Tall, Alan R.
Yvan-Charvet, Laurent
HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders
title HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders
title_full HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders
title_fullStr HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders
title_full_unstemmed HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders
title_short HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders
title_sort hdl and glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570097/
https://www.ncbi.nlm.nih.gov/pubmed/23319699
http://dx.doi.org/10.1084/jem.20121357
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