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

被引：32

作者：

Choudhury, Malay ^{[1
]}

Yin, Xueqian ^{[1
,3
]}

Schaefbauer, Kyle J. ^{[1
]}

Kang, Jeong-Han ^{[1
,4
]}

Roy, Bhaskar ^{[2
]}

Kottom, Theodore J. ^{[1
]}

Limper, Andrew H. ^{[1
]}

Leof, Edward B. ^{[1
]}

机构：

[1] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Thorac Dis Res Unit,Div Pulm & Crit Care Med, Rochester, MN 55905 USA

[2] Mayo Clin, Coll Med, Div Gastroenterol & Hepatol, Rochester, MN USA

[3] Mayo Clin, Coll Med, Dept Mol Med, Rochester, MN USA

[4] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN USA

来源：

FASEB JOURNAL | 2020年 / 34卷 / 07期

关键词：

bleomycin; FOXO4; GLS1; glutamine metabolism; pulmonary fibrosis; SIRT7; TGF-beta signaling; GROWTH-FACTOR-BETA; RECEPTOR; GLUTAMINOLYSIS; METABOLISM; EXPRESSION; GLUTAMATE; CANCER; ACTIVATION; MECHANISMS; RESPONSES;

D O I：

10.1096/fj.202000564R

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

In the current work we show that the profibrotic actions of TGF-beta 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-beta 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-beta. 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-beta. 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-beta-dependent manner.

引用

页码：8920 / 8940

页数：21

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