SIRT7-mediated modulation of glutaminase 1 regulates TGF-β-induced pulmonary fibrosis
SIRT7-mediated modulation of glutaminase 1 regulates TGF-β-induced pulmonary fibrosis
复制标题
DOI：
10.1096/fj.202000564r
复制
发表时间：
2020-06-10
期刊：
影响因子：
4.8
通讯作者：
Leof, Edward B.
中科院分区：
文献类型：
--
作者：
Choudhury, Malay;Yin, Xueqian;Leof, Edward B.
在目前的工作中，我们证明了转化生长因子-β的促纤维化作用至少部分是通过谷氨酰胺代谢的代谢适应不良以及谷氨酰胺酶1(GLS1)的抑制如何逆转肺纤维化来介导的。GLS1在纤维化肺成纤维细胞和正常肺成纤维细胞中高表达，促纤维化靶点的表达、细胞迁移和由转化生长因子-β刺激的软琼脂集落形成需要GLS1活性。此外，抑制Smad2或Smad3以及抑制PI3K、mTORC2和PDGFR可阻断转化生长因子-β诱导的GLS1。我们进一步证明，依赖于NAD的蛋白脱乙酰酶SIRT7和FOXO4转录因子对GLS1的表达起内源性刹车作用，而GLS1表达被转化生长因子-β抑制。最后，给予GLS1抑制剂CB-839可减轻博莱霉素诱导的肺纤维化。我们的研究指出了表观遗传和转录过程之间令人兴奋和未知的联系，这些过程以转化生长因子-β依赖的方式调节谷氨酰胺代谢和纤维化的发展。
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.