MicroRNA-125a/VDR axis impaired autophagic flux and contributed to fibrosis in a CCL4-induced mouse model and patients with liver cirrhosis.

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.