Hexokinase 2 couples glycolysis with the profibrotic actions of TGF-β.

Autor:	Yin X; Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Choudhury M; Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Kang JH; Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Schaefbauer KJ; Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Jung MY; Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Andrianifahanana M; Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Hernandez DM; Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA., Leof EB; Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. leof.edward@mayo.edu.
Jazyk:	angličtina
Zdroj:	Science signaling [Sci Signal] 2019 Dec 17; Vol. 12 (612). Date of Electronic Publication: 2019 Dec 17.
DOI:	10.1126/scisignal.aax4067
Abstrakt:	Metabolic dysregulation in fibroblasts is implicated in the profibrotic actions of transforming growth factor-β (TGF-β). Here, we present evidence that hexokinase 2 (HK2) is important for mediating the fibroproliferative activity of TGF-β both in vitro and in vivo. Both Smad-dependent and Smad-independent TGF-β signaling induced HK2 accumulation in murine and human lung fibroblasts through induction of the transcription factor c-Myc. Knockdown of HK2 or pharmacological inhibition of HK2 activity with Lonidamine decreased TGF-β-stimulated fibrogenic processes, including profibrotic gene expression, cell migration, colony formation, and activation of the transcription factors YAP and TAZ, with no apparent effect on cellular viability. Fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) exhibited an increased abundance of HK2. In a mouse model of bleomycin-induced lung fibrosis, Lonidamine reduced the expression of genes encoding profibrotic markers ( collagen Ια 1 , EDA-fibronectin , α smooth muscle actin , and connective tissue growth factor ) and stabilized or improved lung function as assessed by measurement of peripheral blood oxygenation. These findings provide evidence of how metabolic dysregulation through HK2 can be integrated within the context of profibrotic TGF-β signaling. (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu