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Caveolin-1 scaffolding domain peptide regulates glucose metabolism in lung fibrosis.

Authors
  • Gopu, Venkadesaperumal1
  • Fan, Liang1
  • Shetty, Rashmi1
  • Nagaraja, M R1
  • Shetty, Sreerama1
  • 1 Texas Lung Injury Institute, Department of Medicine, The University of Texas Health Science Center at Tyler, Tyler, United States of America. , (United States)
Type
Published Article
Journal
JCI Insight
Publisher
American Society for Clinical Investigation
Publication Date
Aug 25, 2020
Identifiers
DOI: 10.1172/jci.insight.137969
PMID: 32841217
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Increased metabolism distinguishes myofibroblasts or fibrotic lung fibroblasts (fLfs) from the normal lung fibroblasts (nLfs). The mechanism of metabolic activation in fLfs has not been fully elucidated. Further, the anti-fibrogenic effects of caveolin-1 scaffolding domain peptide CSP/CSP7 involve metabolic reprogramming in fLfs is unclear. We therefore analyzed lactate and succinate levels, and the expression of glycolytic enzymes, and hypoxia inducible factor-1alpha (HIF-1α). Lactate and succinate levels as well as the basal expression of glycolytic enzymes and HIF-1α αwere increased in fLfs. These changes were reversed following restoration of p53 or its transcriptional target microRNA-34a (miR-34a) expression in fLfs. Conversely, inhibition of basal p53 or miR-34a increased glucose metabolism, glycolytic enzymes and HIF-1α in nLfs. Treatment of fLfs or mice having bleomycin- or TGF-beta1-induced lung fibrosis with CSP/CSP7, reduced the expression of glycolytic enzymes and HIF-1α. Further, inhibition of p53 or miR-34a abrogated CSP/CSP7-mediated restoration of glycolytic flux in fLfs in vitro and in mice with pulmonary fibrosis and lacking p53 or miR-34a expression in fibroblasts in vivo. Our data indicate that dysregulation of glucose metabolism in fLfs is causally linked to loss of basal expression of p53 and miR-34a. Treatment with CSP/CSP7 constrains aberrant glucose metabolism through restoration of p53 and miR-34a.

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