Metabolic and Epigenetic Regulation of SMAD7 by STC1 Ameliorates Lung Fibrosis
Metabolic and Epigenetic Regulation of SMAD7 by STC1 Ameliorates Lung Fibrosis
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DOI：
10.1165/rcmb.2021-0445oc
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发表时间：
2022-09-01
影响因子：
6.4
通讯作者：
Okada, Yoshinori
中科院分区：
文献类型：
--
作者：
Ohkouchi, Shinya;Kanehira, Masahiko;Okada, Yoshinori
如我们先前的研究所示，在博来霉素处理的小鼠模型中，STC 1（斯钙素-1）的气管内给药通过呼吸解偶联减少氧化和内质网应激来改善肺纤维化。然而，没有检查STC 1对代谢的总体影响。因此，我们首先进行了全面的代谢组学分析，筛选整体代谢变化诱导的STC 1在肺泡上皮细胞系使用毛细管电泳飞行时间质谱。随后通过对每种物质进行精确分析，在多种肺泡上皮细胞和成纤维细胞系中验证了结果。STC 1刺激糖酵解，乙酰辅酶A的合成，和蛋氨酸和半胱氨酸谷胱甘肽途径，这是密切相关的解偶联呼吸，调制表观遗传学，并减少氧化应激。这些结果与我们以前的研究一致。随后，我们专注于抑制因子SMAD 7，它发挥抗纤维化作用，并容易受到表观遗传调控。STC 1以解偶联蛋白2依赖性方式上调SMAD 7，在人肺泡上皮细胞和成纤维细胞系以及博来霉素处理的小鼠模型中诱导SMAD 7启动子区的去甲基化和SMAD 7蛋白的乙酰化，并且随后减弱纤维化。STC 1的抗纤维化作用可能部分依赖于SMAD 7的调节。在使用来自特发性肺纤维化患者的肺组织的评估中，SMAD 7表达和乙酰化在肺泡结构保留区域中高，而在纤维化区域中低。肺内给药STC 1可能通过调节患者体内代谢介导的SMAD 7表观遗传修饰来预防肺纤维化的发展。
As shown in our previous studies, the intratracheal administration of STC1 (stanniocalcin-1) ameliorates pulmonary fibrosis by reducing oxidative and endoplasmic reticulum stress through the uncoupling of respiration in a bleomycin-treated mouse model. However, the overall effect of STC1 on metabolism was not examined. Therefore, we first conducted a comprehensive metabolomics analysis to screen the overall metabolic changes induced by STC1 in an alveolar epithelial cell line using capillary electrophoresis time-of-flight mass spectrometry. The results were subsequently validated in multiple alveolar epithelial and fibroblast cell lines by performing precise analyses of each substance. STC1 stimulated glycolysis, acetylCoA synthesis, and the methionine and cysteine-glutathione pathways, which are closely related to the uncoupling of respiration, modulation of epigenetics, and reduction in oxidative stress. These results are consistent with our previous study. Subsequently, we focused on the inhibitory factor SMAD7, which exerts an antifibrotic effect and is susceptible to epigenetic regulation. STC1 upregulates SMAD7 in an uncoupling protein 2-dependent manner, induces demethylation of the SMAD7 promoter region and acetylation of the SMAD7 protein in human alveolar epithelial and fibroblast cell lines and a bleomycin-treated mouse model, and subsequently attenuates fibrosis. The antifibrotic effects of STC1 may partially depend on the regulation of SMAD7. In the evaluation using lung tissue from patients with idiopathic pulmonary fibrosis, SMAD7 expression and acetylation were high in the alveolar structure-preserving region and low in the fibrotic region. The intratracheal administration of STC1 may prevent the development of pulmonary fibrosis by regulating the metabolism-mediated epigenetic modification of SMAD7 in patients.