摘要
BACKGROUND Activation of hepatic stellate cells(HSCs)is a pivotal event in the onset and progression of liver fibrosis.Loss of microRNA-194(miR-194)has been reported in activated HSCs,but the actual role of miR-194 in liver fibrosis remains uncertain.AIM To explore the role and potential mechanism of miR-194-mediated regulation of liver fibrosis in vitro and in vivo.METHODS The expression of miR-194 was examined in human fibrotic liver tissues,activated HSCs,and a carbon tetrachloride(CCl4)mouse model by qPCR.The effects of AKT2 regulation by miR-194 on the activation and proliferation of HSCs were assessed in vitro.For in vivo experiments,we reintroduced miR-194 in mice using a miR-194 agomir to investigate the functions of miR-194 in liver fibrosis.RESULTS MiR-194 expression was notably lacking in activated HSCs from both humans and mice.Overexpression of miR-194(OV-miR-194)inhibitedα-smooth muscle actin(α-SMA)and type I collagen(Col I)expression and suppressed cell proliferation in HSCs by causing cell cycle arrest in G0/G1 phase.AKT2 was predicted to be a target of miR-194.Notably,the effects of miR-194 knockdown in HSCs were almost blocked by AKT2 deletion,indicating that miR-194 plays a role in HSCs via regulation of AKT2.Finally,miR-194 agomir treatment dramatically ameliorated liver fibrosis in CCl4-treated mice.CONCLUSION We revealed that miR-194 plays a protective role by inhibiting the activation and proliferation of HSCs via AKT2 suppression.Our results further propose miR-194 as a potential therapeutic target for liver fibrosis.
BACKGROUND Activation of hepatic stellate cells(HSCs) is a pivotal event in the onset and progression of liver fibrosis. Loss of microRNA-194(miR-194) has been reported in activated HSCs, but the actual role of miR-194 in liver fibrosis remains uncertain.AIM To explore the role and potential mechanism of miR-194-mediated regulation of liver fibrosis in vitro and in vivo.METHODS The expression of miR-194 was examined in human fibrotic liver tissues,activated HSCs, and a carbon tetrachloride(CCl4) mouse model by qPCR. The effects of AKT2 regulation by miR-194 on the activation and proliferation of HSCs were assessed in vitro. For in vivo experiments, we reintroduced miR-194 in mice using a miR-194 agomir to investigate the functions of miR-194 in liver fibrosis.RESULTS MiR-194 expression was notably lacking in activated HSCs from both humans and mice. Overexpression of miR-194(OV-miR-194) inhibited α-smooth muscle actin(α-SMA) and type I collagen(Col I) expression and suppressed cell proliferation in HSCs by causing cell cycle arrest in G0/G1 phase. AKT2 was predicted to be a target of miR-194. Notably, the effects of miR-194 knockdown in HSCs were almost blocked by AKT2 deletion, indicating that miR-194 plays a role in HSCs via regulation of AKT2. Finally, miR-194 agomir treatment dramatically ameliorated liver fibrosis in CCl4-treated mice.CONCLUSION We revealed that miR-194 plays a protective role by inhibiting the activation and proliferation of HSCs via AKT2 suppression. Our results further propose miR-194 as a potential therapeutic target for liver fibrosis.
基金
the National Natural Science Foundation of China,No.81600480,No.81570547,and No.81770597
the Development Program of China during the 13th Five-year Plan Period,No.2017ZX10203202003005
