Hepatocyte-specific suppression of microRNA-221-3p mitigates liver fibrosis

肝星状细胞 纤维化 肝细胞 小RNA 癌症研究 基因敲除 下调和上调 生物 肝损伤 肝功能 肝纤维化 肝硬化 内科学 细胞生物学 医学 病理 药理学 内分泌学 细胞凋亡 基因 体外 生物化学
作者
Hsin-Chieh Tsay,Qinggong Yuan,Asha Balakrishnan,Marina Kaiser,Selina Möbus,Emilia Kozdrowska,Marwa Farid,Pia-Katharina Tegtmeyer,Katharina Borst,Florian W. R. Vondran,Ulrich Kalinke,Andreas Kispert,Michael P. Manns,Michael Ott,Amar Deep Sharma
出处
期刊:Journal of Hepatology [Elsevier]
卷期号:70 (4): 722-734 被引量:45
标识
DOI:10.1016/j.jhep.2018.12.016
摘要

Fibrosis, a cardinal feature of a dysfunctional liver, significantly contributes to the ever-increasing mortality due to end-stage chronic liver diseases. The crosstalk between hepatocytes and hepatic stellate cells (HSCs) plays a key role in the progression of fibrosis. Although ample efforts have been devoted to elucidate the functions of HSCs during liver fibrosis, the regulatory functions of hepatocytes remain elusive.Using an unbiased functional microRNA (miRNA) screening, we investigated the ability of hepatocytes to regulate fibrosis by fine-tuning gene expression via miRNA modulation. The in vivo functional analyses were performed by inhibiting miRNA in hepatocytes using adeno-associated virus in carbon-tetrachloride- and 3,5-di-diethoxycarbonyl-1,4-dihydrocollidine-induced liver fibrosis.Blocking miRNA-221-3p function in hepatocytes during chronic liver injury facilitated recovery of the liver and faster resolution of the deposited extracellular matrix. Furthermore, we demonstrate that reduced secretion of C-C motif chemokine ligand 2, as a result of post-transcriptional regulation of GNAI2 (G protein alpha inhibiting activity polypeptide 2) by miRNA-221-3p, mitigates liver fibrosis.Collectively, miRNA modulation in hepatocytes, an easy-to-target cell type in the liver, may serve as a potential therapeutic approach for liver fibrosis.Liver fibrosis majorly contributes to mortality resulting from various liver diseases. We discovered a small RNA known as miRNA-221-3p, whose downregulation in hepatocytes results in reduced liver fibrosis. Thus, inhibition of miRNA-221-3p may serve as one of the therapeutic approaches for treatment of liver fibrosis.
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