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 α8 (ITGA8), and the RhoA signaling pathway on liver fibrosis in NAFLD. After the expression levels of miR-125b-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-125b-5p upregulates ITGA8 expression to activate the RhoA signaling pathway, leading to liver fibrosis in NAFLD.

中文翻译：

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microRNA-125b-5p的表观遗传沉默通过整联蛋白α8介导的RhoA信号通路激活，促进非酒精性脂肪肝疾病的肝纤维化。

背景技术非酒精性脂肪肝疾病（NAFLD）是最常见的慢性肝病之一，其可能会发展为肝纤维化或癌症。本研究旨在研究microRNA-125b-5p（miR-125b-5p）在NAFLD中的作用，并进一步探索潜在的分子机制。方法通过高胆固醇饮食喂养建立NAFLD小鼠模型，并用棕榈酸处理小鼠肝癌细胞系NCTC1469。进行功能增强和功能丧失实验以确定miR-125b-5p，整联蛋白α8（ITGA8）和RhoA信号通路对NAFLD肝纤维化的影响。确定miR-125b-5p，ITGA8和RhoA的表达水平后，在体内和体外评估肝纤维化。然后验证了miR-125b-5p与ITGA8的结合关系。最后，测定了NAFLD肝组织和细胞中的miR-125b-5p启动子甲基化。结果在NAFLD临床样品，小鼠模型和细胞模型中，miR-125b-5p表达降低，而ITGA8表达升高。而且，miR-125b-5p靶向并下调ITGA8，从而导致RhoA信号通路的抑制。在NAFLD肝组织和细胞中，miR-125b-5p启动子中的CpG岛被甲基化，导致miR-125b-5p的表观遗传沉默。miR-125b-5p沉默和ITGA8过表达均通过激活RhoA信号通路在NAFLD体内和体外促进肝纤维化。结论总体而言，miR-125b-5p的表观遗传沉默可上调ITGA8的表达以激活RhoA信号通路，从而导致NAFLD肝纤维化。