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      Glucose Transporter 1–Dependent Glycolysis Is Increased during Aging-Related Lung Fibrosis, and Phloretin Inhibits Lung Fibrosis

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          Abstract

          Aging is associated with metabolic diseases such as type 2 diabetes mellitus, cardiovascular disease, cancer, and neurodegeneration. Aging contributes to common processes including metabolic dysfunction, DNA damage, and reactive oxygen species generation. Although glycolysis has been linked to cell growth and proliferation, the mechanisms by which the activation of glycolysis by aging regulates fibrogenesis in the lung remain unclear. The objective of this study was to determine if glucose transporter 1 (GLUT1)–induced glycolysis regulates age-dependent fibrogenesis of the lung. Mouse and human lung tissues were analyzed for GLUT1 and glycolytic markers using immunoblotting. Glycolytic function was measured using a Seahorse apparatus. To study the effect of GLUT1, genetic inhibition of GLUT1 was performed by short hairpin RNA transduction, and phloretin was used for pharmacologic inhibition of GLUT1. GLUT1-dependent glycolysis is activated in aged lung. Genetic and pharmacologic inhibition of GLUT1 suppressed the protein expression of α-smooth muscle actin, a key cytoskeletal component of activated fibroblasts, in mouse primary lung fibroblast cells. Moreover, we demonstrated that the activation of AMP-activated protein kinase, which is regulated by GLUT1-dependent glycolysis, represents a critical metabolic pathway for fibroblast activation. Furthermore, we demonstrated that phloretin, a potent inhibitor of GLUT1, significantly inhibited bleomycin-induced lung fibrosis in vivo. These results suggest that GLUT1-dependent glycolysis regulates fibrogenesis in aged lung and that inhibition of GLUT1 provides a potential target of therapy of age-related lung fibrosis.

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          Author and article information

          Journal
          Am J Respir Cell Mol Biol
          Am. J. Respir. Cell Mol. Biol
          ajrcmb
          American Journal of Respiratory Cell and Molecular Biology
          American Thoracic Society
          1044-1549
          1535-4989
          April 2017
          April 2017
          : 56
          : 4
          : 521-531
          Affiliations
          [ 1 ]Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York
          [ 2 ]Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York; and
          [ 3 ]Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island
          Author notes
          Correspondence and requests for reprints should be addressed to Heather W. Stout-Delgado, Ph.D., Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, 525 East 68th Street, Box 96, New York, NY 10065. E-mail: hes2019@ 123456med.cornell.edu
          Article
          PMC5449513 PMC5449513 5449513 2016-0225OC
          10.1165/rcmb.2016-0225OC
          5449513
          27997810
          249793a0-33e5-4837-8196-e70afcc8c903
          Copyright © 2017 by the American Thoracic Society
          History
          : 20 July 2016
          : 15 December 2016
          Page count
          Figures: 7, Tables: 0, Pages: 11
          Categories
          Original Research

          idiopathic pulmonary fibrosis,glucose metabolism,bleomycin

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