Wei He1, Weijie Ni2, Lili Zhao3, Xiang Wang3, Li Liu3, Zhining Fan4. 1. 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. Electronic address: bingbing_he@yeah.net. 2. School of Medicine, Southeast University, Nanjing 210029, Jiangsu Province, China. 3. 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. 4. 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. Electronic address: fanzhining@njmu.edu.cn.
Abstract
AIMS: To clarify the role of the miR-125a/VDR axis in the regulation of autophagic flux in hepatocytes and liver fibrosis. MAIN METHODS: 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. KEY FINDINGS: 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. SIGNIFICANCE: 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.
AIMS: To clarify the role of the miR-125a/VDR axis in the regulation of autophagic flux in hepatocytes and liver fibrosis. MAIN METHODS: 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. KEY FINDINGS: 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 humanliver 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. SIGNIFICANCE: 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.