Department of Gastroenterology, Geriatric Hospital of Nanjing Medical University, Jiangsu Province Geriatric Institute, Jiangsu Province Official Hospital, Nanjing 210024, Jiangsu Province, China; Department of Digestive Endoscopy, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, Jiangsu Province, China; Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
School of Medicine, Southeast University, Nanjing 210029, Jiangsu Province, China.
Life Sci. 2021 Jan 1;264:118666. doi: 10.1016/j.lfs.2020.118666. Epub 2020 Oct 29.
To clarify the role of the miR-125a/VDR axis in the regulation of autophagic flux in hepatocytes and liver fibrosis.
The effects of the miR-125a/VDR axis on hepatic fibrosis and its underlying mechanisms were investigated in a carbon tetrachloride (CCl4)-induced mouse model and patients with liver cirrhosis by immunohistochemistry, real-time PCR, Western blotting, and luciferase reporter assay.
The degree of fibrosis in patients with liver cirrhosis was negatively correlated with VDR expression and autophagic flux in hepatocytes. Luciferase reporter assays confirmed that VDR is a direct target of miR-125a, which was positively correlated with the degree of fibrosis but negatively correlated with the autophagic flux and VDR expression in human liver cirrhosis tissue. miR-125a-antagomir-GFP AAV treatment partially restored VDR expression and autophagic flux and abrogated fibrosis in the liver of CCL4-induced mouse. In addition, knockdown of VDR abrogated the protective effect of miR-125a-antagomir-GFP AAV on autophagic flux and against liver fibrosis in the CCL4-induced mouse model.
Our study for the first time identified the miR-125a/VDR axis as involved in the occurrence and development of liver fibrosis by regulating autophagic flux in hepatocytes.
阐明 miR-125a/VDR 轴在肝细胞自噬流调控中的作用及其在肝纤维化中的作用机制。
通过免疫组织化学、实时 PCR、Western blot 和荧光素酶报告基因检测，研究 miR-125a/VDR 轴在四氯化碳（CCl4）诱导的小鼠模型和肝硬化患者中对肝纤维化的影响及其潜在机制。
肝硬化患者的纤维化程度与 VDR 表达和肝细胞自噬流呈负相关。荧光素酶报告基因检测证实 VDR 是 miR-125a 的直接靶标，与纤维化程度呈正相关，但与肝硬化患者肝组织中的自噬流和 VDR 表达呈负相关。miR-125a-antagomir-GFP AAV 治疗部分恢复了 VDR 表达和自噬流，并减轻了 CCl4 诱导的小鼠肝脏纤维化。此外，敲低 VDR 可消除 miR-125a-antagomir-GFP AAV 对自噬流和 CCl4 诱导的小鼠模型肝纤维化的保护作用。
本研究首次发现 miR-125a/VDR 轴通过调节肝细胞自噬流参与肝纤维化的发生发展。
Zotero 插件