@article{2421dc9e2f424155b702f901b15e20d0,
title = "SIRT7-mediated modulation of glutaminase 1 regulates TGF-β-induced pulmonary fibrosis",
abstract = "In the current work we show that the profibrotic actions of TGF-β are mediated, at least in part, through a metabolic maladaptation in glutamine metabolism and how the inhibition of glutaminase 1 (GLS1) reverses pulmonary fibrosis. GLS1 was found to be highly expressed in fibrotic vs normal lung fibroblasts and the expression of profibrotic targets, cell migration, and soft agar colony formation stimulated by TGF-β required GLS1 activity. Moreover, knockdown of SMAD2 or SMAD3 as well as inhibition of PI3K, mTORC2, and PDGFR abrogated the induction of GLS1 by TGF-β. We further demonstrated that the NAD-dependent protein deacetylase, SIRT7, and the FOXO4 transcription factor acted as endogenous brakes for GLS1 expression, which are inhibited by TGF-β. Lastly, administration of the GLS1 inhibitor CB-839 attenuated bleomycin-induced pulmonary fibrosis. Our study points to an exciting and unexplored connection between epigenetic and transcriptional processes that regulate glutamine metabolism and fibrotic development in a TGF-β-dependent manner.",
keywords = "FOXO4, GLS1, SIRT7, TGF-β signaling, bleomycin, glutamine metabolism, pulmonary fibrosis",
author = "Malay Choudhury and Xueqian Yin and Schaefbauer, {Kyle J.} and Kang, {Jeong Han} and Bhaskar Roy and Kottom, {Theodore J.} and Limper, {Andrew H.} and Leof, {Edward B.}",
note = "Funding Information: We would like to thank Dr Carol Feghali‐Bostwick (Medical University of South Carolina, Charleston, SC) and Dr Nathan Sandbo (University of Wisconsin‐Madison, Madison, WI) for providing primary fibroblasts from normal donors and IPF patients. This work was supported by Public Health Service Grants GM‐54200 and GM‐55816 from the National Institute of General Medical Sciences, the Caerus Foundation (91736058), and the Mayo Foundation (EBL). The research leading to these results received support of the “Brewer Family Career Development Award in Support of Idiopathic Pulmonary Fibrosis and Related Interstitial Lung Disease Research” (MC). Funding Information: We would like to thank Dr Carol Feghali-Bostwick (Medical University of South Carolina, Charleston, SC) and Dr Nathan Sandbo (University of Wisconsin-Madison, Madison, WI) for providing primary fibroblasts from normal donors and IPF patients. This work was supported by Public Health Service Grants GM-54200 and GM-55816 from the National Institute of General Medical Sciences, the Caerus Foundation (91736058), and the Mayo Foundation (EBL). The research leading to these results received support of the ?Brewer Family Career Development Award in Support of Idiopathic Pulmonary Fibrosis and Related Interstitial Lung Disease Research? (MC). Publisher Copyright: {\textcopyright} 2020 Federation of American Societies for Experimental Biology Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = jul,
day = "1",
doi = "10.1096/fj.202000564R",
language = "English (US)",
volume = "34",
pages = "8920--8940",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "7",
}