SIRT7-mediated modulation of glutaminase 1 regulates TGF-β-induced pulmonary fibrosis.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Malay ChoudhuryEdward B Leof

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.

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Citations

Sep 15, 2020·Molecular Diagnosis & Therapy·Krystian BartczakWojciech J Piotrowski
Jan 5, 2021·The FEBS Journal·Robert B Hamanaka, Gökhan M Mutlu
May 25, 2021·Trends in Endocrinology and Metabolism : TEM·John Henderson, Steven O'Reilly
Aug 27, 2021·Cellular Signalling·Alexis Paulina Jiménez-UribeJosé Pedraza-Chaverri

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