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Hexokinase 2 couples glycolysis with the profibrotic actions of TGF-β.
Science Signaling ( IF 7.3 ) Pub Date : 2019-12-17 , DOI: 10.1126/scisignal.aax4067
Xueqian Yin 1 , Malay Choudhury 1 , Jeong-Han Kang 1 , Kyle J Schaefbauer 1 , Mi-Yeon Jung 1 , Mahefatiana Andrianifahanana 1 , Danielle M Hernandez 1 , Edward B Leof 1
Affiliation  

Metabolic dysregulation in fibroblasts is implicated in the profibrotic actions of transforming growth factor-β (TGF-β). Here, we present evidence that hexokinase 2 (HK2) is important for mediating the fibroproliferative activity of TGF-β both in vitro and in vivo. Both Smad-dependent and Smad-independent TGF-β signaling induced HK2 accumulation in murine and human lung fibroblasts through induction of the transcription factor c-Myc. Knockdown of HK2 or pharmacological inhibition of HK2 activity with Lonidamine decreased TGF-β-stimulated fibrogenic processes, including profibrotic gene expression, cell migration, colony formation, and activation of the transcription factors YAP and TAZ, with no apparent effect on cellular viability. Fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) exhibited an increased abundance of HK2. In a mouse model of bleomycin-induced lung fibrosis, Lonidamine reduced the expression of genes encoding profibrotic markers (collagenΙα1, EDA-fibronectin, α smooth muscle actin, and connective tissue growth factor) and stabilized or improved lung function as assessed by measurement of peripheral blood oxygenation. These findings provide evidence of how metabolic dysregulation through HK2 can be integrated within the context of profibrotic TGF-β signaling.

中文翻译:

己糖激酶2将糖酵解与TGF-β的纤维化作用结合在一起。

成纤维细胞的代谢失调与转化生长因子-β(TGF-β)的促纤维化作用有关。在这里,我们提供的证据表明,己糖激酶2(HK2)对于介导TGF-β在体外和体内的纤维增生活性都很重要。Smad依赖和Smad依赖的TGF-β信号均通过诱导转录因子c-Myc诱导HK2在鼠和人肺成纤维细胞中的蓄积。敲除HK2或用Lonidamine抑制HK2活性会降低TGF-β刺激的纤维化过程,包括纤维化基因表达,细胞迁移,集落形成以及转录因子YAP和TAZ的激活,而对细胞生存力没有明显影响。患有特发性肺纤维化(IPF)的患者的成纤维细胞显示HK2的丰度增加。在博来霉素诱导的肺纤维化的小鼠模型中,Lonidamine降低了编码纤维化标记物(胶原蛋白α1,EDA-纤连蛋白,α平滑肌肌动蛋白和结缔组织生长因子)的基因的表达,并通过测量外周血来稳定或改善了肺功能血液氧合。这些发现提供了在纤维化TGF-β信号转导的背景下如何整合通过HK2的代谢失调的证据。
更新日期:2019-12-18
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