Targeting Pulmonary Fibrosis by SLC1A5-Dependent Glutamine Transport Blockade.
Targeting Pulmonary Fibrosis by SLC1A5-Dependent Glutamine Transport Blockade.
复制标题
通过 SLC1A5 依赖性谷氨酰胺转运阻断来治疗肺纤维化。
DOI：
10.1165/rcmb.2022-0339oc
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发表时间：
2023
影响因子：
6.4
通讯作者：
Limper,AndrewH
中科院分区：
文献类型：
--
作者：
Choudhury,Malay;Schaefbauer,KyleJ;Kottom,TheodoreJ;Yi,EunheeS;Tschumperlin,DanielJ;Limper,AndrewH
中性氨基酸谷氨酰胺在 TGF-β（转化生长因子-β）诱导的肌成纤维细胞活化和分化中发挥核心作用。细胞主要通过细胞表面表达的转运蛋白摄取谷氨酰胺，称为溶质载体SLC1A5（溶质载体转运蛋白1A5）。在目前的工作中，我们证明了 TGF-β 的促纤维化作用至少部分是通过 SLC1A5 的代谢适应不良介导的，并且靶向 SLC1A5 消除了成纤维细胞激活的多个方面。因此，这种方法可以代表一种治疗纤维增殖性疾病患者的新治疗策略。我们发现SLC1A5在纤维化肺成纤维细胞和从特发性肺纤维化肺中分离的成纤维细胞中高表达。 TGF-β 促纤维化靶标的表达、细胞迁移和不依赖贴壁的生长需要 SLC1A5 的活性。 SLC1A5功能的丧失或抑制会增强成纤维细胞对自噬的敏感性；抑制 mTOR、HIF（缺氧诱导因子）和 Myc 信号传导；线粒体功能、ATP 生成和糖酵解受损。在博来霉素治疗的小鼠肺纤维化模型中，小分子抑制剂 V-9302 对 SLC1A5 的药理抑制作用使成纤维细胞转录谱从促纤维化转变为纤维化消退和减弱。据我们所知，这是第一项证明谷氨酰胺转运药理学抑制剂在纤维化中的效用的研究，为针对这种破坏性疾病的细胞代谢的新范式转变疗法提供了框架。
The neutral amino acid glutamine plays a central role in TGF-β (transforming growth factor-β)–induced myofibroblast activation and differentiation. Cells take up glutamine mainly through a transporter expressed on the cell surface known as solute carrier SLC1A5 (solute carrier transporter 1A5). In the present work, we demonstrated that profibrotic actions of TGF-β are mediated, at least in part, through a metabolic maladaptation of SLC1A5 and that targeting SLC1A5 abrogates multiple facets of fibroblast activation. This approach could thus represent a novel therapeutic strategy to treat patients with fibroproliferative diseases. We found that SLC1A5 was highly expressed in fibrotic lung fibroblasts and fibroblasts isolated from idiopathic pulmonary fibrosis lungs. The expression of profibrotic targets, cell migration, and anchorage-independent growth by TGF-β required the activity of SLC1A5. Loss or inhibition of SLC1A5 function enhanced fibroblast susceptibility to autophagy; suppressed mTOR, HIF (hypoxia-inducible factor), and Myc signaling; and impaired mitochondrial function, ATP production, and glycolysis. Pharmacological inhibition of SLC1A5 by the small-molecule inhibitor V-9302 shifted fibroblast transcriptional profiles from profibrotic to fibrosis resolving and attenuated fibrosis in a bleomycin-treated mouse model of lung fibrosis. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in fibrosis, providing a framework for new paradigm-shifting therapies targeting cellular metabolism for this devastating disease.