MicroRNA-101 suppresses liver fibrosis by downregulating PI3K/Akt/mTOR signaling pathway

Background: MicroRNA-101 (miR-101) is markedly downregulated in both hepatitis B virus- related liver cirrhosis and hepatocellular carcinoma (HCC). In this study, we aimed to investigate the effect and mechanism of miR-101 on hepatic stellate cell (HSC) activation and liver fibrosis. Materials and methods: HSC LX-2 was treated with TGF-beta 1 and with or without miR-101 mimics. LX-2 vitality and proliferation, the expression of F-actin and mRNAs for alpha-SMA, collagen 1 alpha 1 (Cot 1 alpha 1), and connective tissue growth factor 2 (CCN2) were measured. A 6-week intraperitoneal injection of carbon tetrachloride (CCl4) was used to induce experimental liver fibrosis in mice, which were treated using a miR-101 negative control or miR-101 agomir from the fourth week until the end of the experiment. Liver function, hepatic hydroxyproline, liver histopathology, collagen deposition, alpha-SMA, type I collagen (Col I) and the protein-expressions of p-PI3K, p-Akt and p-mTOR were measured. Results: MiR-101 significantly suppressed the increased LX-2 vitality and high accumulation of extracellular matrix (ECM) induced by TGF-beta 1 . Exposure to CCl4 led to the impairment of liver function and disruption of normal hepatic parenchyma in mice, as well as obvious liver fibrosis indicated by elevated levels of hydroxyproline, alpha-SMA, and Col 1 alpha 1 in liver tissues. MiR-101 administration significantly improved liver function, relieved hepatic parenchyma damage, and reversed liver fibrosis by decreasing the accumulation of ECM components. Furthermore, rniR-101 substantially downregulated the CCl4-increased p-PI3K, p-Akt, and p-mTOR in mouse liver. Conclusions: MiR-101 has antifibrotic effects in experimental liver fibrosis, and downregulating the PI3K/Akt/mTOR signaling pathway may be one of its antifibrotic mechanisms. (C) 2019 Published by Elsevier Masson SAS.