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

• Published in: Journal of hepatology Vol. 70; no. 4; pp. 722 - 734
• Main Authors: Tsay, Hsin-Chieh, Yuan, Qinggong, Balakrishnan, Asha, Kaiser, Marina, Möbus, Selina, Kozdrowska, Emilia, Farid, Marwa, Tegtmeyer, Pia-Katharina, Borst, Katharina, Vondran, Florian W.R., Kalinke, Ulrich, Kispert, Andreas, Manns, Michael P., Ott, Michael, Sharma, Amar Deep
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2019; Elsevier Science Ltd
• Subjects: Animals; Bile; Carbon Tetrachloride - pharmacology; Chemokine ligands; Chemokines; Dependovirus - genetics; Down-Regulation - genetics; Extracellular matrix; Extracellular Matrix - metabolism; Female; Fibrosis; Gene expression; Gene Expression Regulation; Gene regulation; HEK293 Cells; Hepatic stellate cells; Hepatic Stellate Cells - metabolism; Hepatocytes; Hepatocytes - metabolism; Humans; Liver Cirrhosis, Experimental - chemically induced; Liver Cirrhosis, Experimental - metabolism; Liver Cirrhosis, Experimental - pathology; Liver diseases; Mice; Mice, Inbred BALB C; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; miRNA-221-3p; Mortality; Post-transcription; Stellate cells; Transfection; miRNA; Hepatic stellate cells; miRNA-221-3p; Chemokine ligands; Fibrosis
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2018.12.016

[Display omitted] •Identification of microRNA-221-3p as a regulator of liver fibrosis in vitro.•Inhibition of microRNA-221-3p in hepatocytes is capable of reducing liver fibrosis in mouse models.•Treatment of primary human hepatocytes with microRNA-221 inhibitor suppresses activation of human myofibroblasts. 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.