title: Glucose Transporter 1-Dependent Glycolysis Is Increased during Aging-Related Lung Fibrosis, and Phloretin Inhibits Lung Fibrosis.
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.
authors.affiliation: 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.
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Cho
authors.affiliation: 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.
authors.forename: Jong-Seok
authors.initials: JS
authors.lastname: Moon
authors.affiliation: 3 Department of Molecular Microbiology and Immunology, Brown University, Providence, Rhode Island.
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.affiliation: 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.
authors.forename: Heather W
authors.initials: HW
authors.lastname: Stout-Delgado
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001761:Bleomycin; D016922:Cellular Senescence; D004789:Enzyme Activation / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D010693:Phloretin / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D051272:Glucose Transporter Type 1; D001761:Bleomycin; D055372:AMP-Activated Protein Kinases; D010693:Phloretin
keywords: bleomycin; glucose metabolism; idiopathic pulmonary fibrosis