microRNA-34a and microRNA-34c promote the activation of human hepatic stellate cells by targeting peroxisome proliferator-activated receptor γ

Liver fibrosis is the common outcome of almost all cases of chronic liver disease. The hallmark of liver fibrosis is the activation of hepatic stellate cells (HSCs). microRNA-34a (miR-34a), which regulates a plethora of target proteins involved in the cell cycle, apoptosis, differentiation and cellular development, is found to be upregulated in both activated HSCs and liver fibrosis, while it is consistently downregulated in numerous cancer types. In the present study, the possible mechanisms underlying the role of miR-34a and miR-34c in the activation of the HSCs was investigated. Through bioinformatics analysis and a luciferase reporter assay, five genes were identified to be the target genes of miR-34a and miR-34c. Of these, peroxisome proliferator-activated receptor gamma (PPAR gamma) was selected for further investigation. Mutation luciferase reporter assay confirmed the direct interaction of PPAR gamma and miR-34a and miR-34-c. Western blot analysis and quantitative polymerase chain reaction demonstrated that the expression of PPAR gamma was negatively correlated with the expression of miR-34a and miR-34c during the activation of HSCs. In activated human HSCs, inhibitors of miR-34a and miR-34c upregulated the expression of PPAR gamma and downregulated the expression of alpha-smooth muscle actin. These data suggested that the miR-34 family may be involved the process of liver fibrosis by targeting PPAR gamma.