Metformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis
Metformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis
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DOI：
10.1038/s41467-019-10839-0
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发表时间：
2019-07-05
影响因子：
16.6
通讯作者：
El Agha, Elie
中科院分区：
文献类型：
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作者：
Kheirollahi, Vahid;Wasnick, Roxana M.;El Agha, Elie
特发性肺纤维化（IPF）是一种致命性疾病，其中复杂的肺泡网络逐渐被纤维化瘢痕取代。肌成纤维细胞是过度存款细胞外基质蛋白从而损害肺结构和功能的效应细胞。新出现的文献表明IPF中纤维化与代谢改变之间存在相关性。在这项研究中，我们发现一线抗糖尿病药物二甲双胍通过调节代谢途径、抑制TGF β 1作用、抑制胶原蛋白形成、激活PPAR γ信号传导和诱导IPF患者肺成纤维细胞的脂肪生成分化，在肺中发挥强效抗纤维化作用。在小鼠肺纤维化模型中使用遗传谱系追踪，我们表明二甲双胍通过诱导肌成纤维细胞向脂成纤维细胞转分化改变肌成纤维细胞的命运并加速纤维化消退。详细的通路分析揭示了二甲双胍加速纤维化消退的双臂机制。我们的数据报告了二甲双胍在肺中的抗纤维化作用，因此需要进一步的治疗评价。
Idiopathic pulmonary fibrosis (IPF) is a fatal disease in which the intricate alveolar network of the lung is progressively replaced by fibrotic scars. Myofibroblasts are the effector cells that excessively deposit extracellular matrix proteins thus compromising lung structure and function. Emerging literature suggests a correlation between fibrosis and metabolic alterations in IPF. In this study, we show that the first-line antidiabetic drug metformin exerts potent antifibrotic effects in the lung by modulating metabolic pathways, inhibiting TGF beta 1 action, suppressing collagen formation, activating PPAR gamma signaling and inducing lipogenic differentiation in lung fibroblasts derived from IPF patients. Using genetic lineage tracing in a murine model of lung fibrosis, we show that metformin alters the fate of myofibroblasts and accelerates fibrosis resolution by inducing myofibroblast-to-lipofibroblast transdifferentiation. Detailed pathway analysis revealed a two-arm mechanism by which metformin accelerates fibrosis resolution. Our data report an antifibrotic role for metformin in the lung, thus warranting further therapeutic evaluation.