Life sciences · 2020
MicroRNA-125a/VDR axis impaired autophagic flux and contributed to fibrosis in a CCL4-induced mouse model and patients with liver cirrhosis.
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He Wei, Ni Weijie, Zhao Lili, Wang Xiang, Liu Li, Fan Zhining
Аннотация
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.
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.