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Glucose Transporter 1–Dependent Glycolysis Is Increased during Aging-Related Lung Fibrosis, and Phloretin Inhibits Lung Fibrosis
Open accessAbstract
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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“Specifically, aged fibroblasts have augmented glucose utilization and increased resistance to apoptosis, which may underlie increased susceptibility of the aged lung to fibrogenesis (144).”
From Aging and Lung Disease (2020) · cites this paper as [144]
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Metadata
- Authors
- Cho, S. J., Moon, J.-S., Lee, C.-M., Choi, A. M. K., & Stout-Delgado, H. W.
- Affiliations
- NewYork–Presbyterian Hospital (US)
- Brown University (US)
- Corresponding author
- Stout-Delgado, Heather W.
- Venue
- American Journal of Respiratory Cell and Molecular Biology
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-04-01
- Volume
- 56
- Issue
- 4
- Pages
- 521-531
- ISSN
- 1044-1549 (ISSN-L)
- 1535-4989
- PMC
- PMC5449513
- OpenAlex
- W2576471964
- Cited by
- 133
- References
- 46
- Citations by year
- 2026: 14 · 2025: 11 · 2024: 17 · 2023: 16 · 2022: 14 · 2021: 24 · 2020: 17 · 2019: 11 · 2018: 6 · 2017: 3
- FWCI
- 8.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Respiratory Cell and Molecular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (L30 AG043118, R21AG044755, K01AG034999)
- National Heart, Lung, and Blood Institute (P01HL114501)
- National Institute of Allergy and Infectious Diseases (T32AI007613)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- glucose transporter 1, GLUT1, glycolysis, pulmonary fibrosis, aging, phloretin, AMPK, fibroblast activation, alpha-smooth muscle actin, bleomycin-induced fibrosis, metabolic reprogramming, therapeutic target
- MeSH terms
- Aging, Animals, Bleomycin, Enzyme Activation, Glycolysis, Male, Mice, Inbred C57BL, Phloretin, Phosphorylation, Pulmonary Fibrosis, Cellular Senescence, Glucose Transporter Type 1, AMP-Activated Protein Kinases
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