Yang Lei1, Qing-Lan Wang2, Li Shen2, Yan-Yan Tao3, Cheng-Hai Liu4. 1. Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China; Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200040, PR China. 2. Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China. 3. Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China. Electronic address: taoyanyan1023@126.com. 4. Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai 201203, PR China; Shanghai Innovation Center of TCM Health Service, Shanghai 201203, PR China. Electronic address: chenghailiu@hotmail.com.
Abstract
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-β1 and with or without miR-101 mimics. LX-2 vitality and proliferation, the expression of F-actin and mRNAs for α-SMA, collagen 1α1 (Col 1α1), 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, α-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-β1. 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, α-SMA, and Col 1α1 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, miR-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.
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-β1 and with or without miR-101 mimics. LX-2 vitality and proliferation, the expression of F-actin and mRNAs for α-SMA, collagen 1α1 (Col 1α1), 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, α-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-β1. 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, α-SMA, and Col 1α1 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, miR-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.
Authors: Eleftheria M Mastoridou; Anna C Goussia; Georgios K Glantzounis; Panagiotis Kanavaros; Antonia V Charchanti Journal: Front Physiol Date: 2022-02-03 Impact factor: 4.566