Epigenetic silencing of microRNA-125b-5p promotes liver fibrosis in nonalcoholic fatty liver disease via integrin α8-mediated activation of RhoA signaling pathway
Epigenetic silencing of microRNA-125b-5p promotes liver fibrosis in nonalcoholic fatty liver disease via integrin α8-mediated activation of RhoA signaling pathway
复制标题
microRNA-125b-5p的表观遗传沉默通过整合素α8介导的RhoA信号通路激活促进非酒精性脂肪性肝病的肝纤维化
DOI：
10.1016/j.metabol.2020.154140
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发表时间：
2020-03-01
影响因子：
9.8
通讯作者：
He, Qing
中科院分区：
文献类型：
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作者：
Cai, Qingxian;Chen, Fengjuan;He, Qing
背景：非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病之一，可进展为肝纤维化或肝癌。本研究旨在探讨microRNA-125 b-5 p（miR-125 b-5 p）在NAFLD中的作用，并进一步探讨其分子机制。进行功能获得和丧失实验以确定miR-125 b-5 p、整合素α 8（FTGA 8）和RhoA信号传导途径对NAFLD中肝纤维化的影响。在确定miR-1256- 5 p、ITGA 8和RhoA的表达水平后，在体内和体外评估肝纤维化。然后验证miR-125 b-5 p和ITGA 8的结合关系。结果：在NAFLD临床标本、小鼠模型和细胞模型中，miR-125 b-5 p表达降低，而ITGA 8表达升高。此外，miR-125 b-5 p靶向并下调ITGA 8，导致RhoA信号通路的抑制。在NAFLD肝组织和细胞中，miR-125 b-5 p启动子中的CpG岛被甲基化，导致miR-125 b-5 p的表观遗传沉默。miR-125 b-5 p沉默和ITGA 8过表达均通过激活RhoA信号通路促进了体外和体内NAFLD中的肝纤维化。结论：总体而言，miR-1256- 5 p的表观遗传沉默上调ITGA 8表达以激活RhoA信号通路，导致NAFLD中的肝纤维化。(C)2020爱思唯尔公司All rights reserved.
Background: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases that may progress to liver fibrosis or cancer. The present study aimed to investigate the role of microRNA-125b-5p (miR-125b-5p) in NAFLD and to further explore underlying molecular mechanisms.Methods: A mouse model of NAFLD was constructed by high cholesterol diet feeding and a cell-model was developed by treating the mouse liver cell line NCTC1469 with palmitic acid. Gain- and loss-of-function experiments were performed to determine the effects of miR-125b-5p, integrin alpha 8 (FTGA8), and the RhoA signaling pathway on liver fibrosis in NAFLD. After the expression levels of miR-1256-5p, ITGA8, and RhoA were determined, liver fibrosis was evaluated in vivo and in vitro. The binding relationship of miR-125b-5p and ITGA8 was then validated. Finally, miR-125b-5p promoter methylation in NAFLD liver tissues and cells was determined.Results: In NAFLD clinical samples, mouse model, and cell-model, miR-125b-5p expression was reduced, while ITGA8 expression was increased. Moreover, miR-125b-5p targeted and downregulated ITGA8, leading to inhibition of the RhoA signaling pathway. In NAFLD liver tissues and cells, the CpG island in the miR-125b-5p promoter was methylated, causing epigenetic silencing of miR-125b-5p. Both miR-125b-5p silencing and ITGA8 overexpression promoted in vitro and in vivo liver fibrosis in NAFLD via activation of the RhoA signaling pathway.Conclusions: Collectively, epigenetic silencing of miR-1256-5p upregulates ITGA8 expression to activate the RhoA signaling pathway, leading to liver fibrosis in NAFLD. (C) 2020 Elsevier Inc. All rights reserved.