miR-345-5p curbs hepatic stellate cell activation and liver fibrosis progression by suppressing hypoxia-inducible factor-1alpha expression

Abstract

Hepatic fibrosis, as a common stage of multiple liver diseases, currently has no effective drug treatment. Emerging evidence shows that miRNAs participate in the progression of liver fibrosis. However, the potential role of miRNAs in hepatic fibrosis is not yet fully understood. Herein, we first confirmed that miR-345-5p expression was significantly decreased in activated hepatic stellate cells (HSCs) and fibrotic livers. Functional analysis showed that overexpression of miR-345-5p in human LX-2 cells suppressed the expression of profibrotic markers and cellular proliferation in vitro. Using a dual-luciferase assay, we demonstrated that miR-345-5p regulates HSC activation by targeting the 3'UTR of HIF-1α mRNA. In addition, overexpression of miR-345-5p in vivo alleviated murine liver fibrosis induced by carbon tetrachloride (CCl4) injection, high-fat diet (HFD) feeding and bile duct ligation (BDL). Furthermore, overexpression of miR-345-5p downregulated the expression of HIF-1α and fibrosis markers in livers from different fibrosis models. Collectively, we conclude that miR-345-5p mediates the activation of HSCs by targeting HIF-1α, which subsequently modulates TGFβ/Smad2/Smad3 signaling. Thus, miR-345-5p may become a novel therapeutic target for the treatment of liver fibrosis.

Keywords: Hepatic stellate cell; Hypoxia-inducible factor-1alpha; Liver fibrosis; MiR-345–5p.