title: Profibrotic up-regulation of glucose transporter 1 by TGF-β involves activation of MEK and mammalian target of rapamycin complex 2 pathways.
abstract: TGF-β plays a central role in the pathogenesis of fibroproliferative disorders. Defining the exact underlying molecular basis is therefore critical for the development of viable therapeutic strategies. Here, we show that expression of the facilitative glucose transporter 1 (GLUT1) is induced by TGF-β in fibroblast lines and primary cells and is required for the profibrotic effects of TGF-β. In addition, enhanced GLUT1 expression is observed in fibrotic areas of lungs of both patients with idiopathic pulmonary fibrosis and mice that are subjected to a fibrosis-inducing bleomycin treatment. By using pharmacologic and genetic approaches, we demonstrate that up-regulation of GLUT1 occurs via the canonical Smad2/3 pathway and requires autocrine activation of the receptor tyrosine kinases, platelet-derived and epidermal growth factor receptors. Engagement of the common downstream effector PI3K subsequently triggers activation of the MEK and mammalian target of rapamycin complex 2, which cooperate in regulating GLUT1 expression. Of note, inhibition of GLUT1 activity and/or expression is shown to impair TGF-β-driven fibrogenic processes, including cell proliferation and production of profibrotic mediators. These findings provide new perspectives on the interrelation of metabolism and profibrotic TGF-β signaling and present opportunities for potential therapeutic intervention.-Andrianifahanana, M., Hernandez, D. M., Yin, X., Kang, J.-H., Jung, M.-Y., Wang, Y., Yi, E. S., Roden, A. C., Limper, A. H., Leof, E. B. Profibrotic up-regulation of glucose transporter 1 by TGF-β involves activation of MEK and mammalian target of rapamycin complex 2 pathways.
authors.affiliation: Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Mahefatiana
authors.initials: M
authors.lastname: Andrianifahanana
authors.affiliation: Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Hernandez
authors.affiliation: Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Xueqian
authors.initials: X
authors.lastname: Yin
authors.affiliation: Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Jeong-Han
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Jung
authors.affiliation: Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.|Division of Nephrology, Augusta University, Augusta, Georgia, USA.
authors.forename: Youli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Eunhee S
authors.initials: ES
authors.lastname: Yi
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Anja C
authors.initials: AC
authors.lastname: Roden
authors.affiliation: Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Limper
authors.affiliation: Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; leof.edward@mayo.edu.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Leof
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051272:Glucose Transporter Type 1; C495678:Slc2a1 protein, mouse; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020123:Sirolimus
keywords: fibrosis; metabolism; signaling