Hepatocyte-specific suppression of microRNA-221-3p mitigates liver fibrosis.
Animals
Carbon Tetrachloride
/ pharmacology
Dependovirus
/ genetics
Down-Regulation
/ genetics
Extracellular Matrix
/ metabolism
Female
Gene Expression Regulation
HEK293 Cells
Hepatic Stellate Cells
/ metabolism
Hepatocytes
/ metabolism
Humans
Liver Cirrhosis, Experimental
/ chemically induced
Mice
Mice, Inbred BALB C
MicroRNAs
/ genetics
Transfection
Chemokine ligands
Fibrosis
Hepatic stellate cells
miRNA
miRNA-221-3p
Journal
Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
04
01
2018
revised:
02
12
2018
accepted:
10
12
2018
pubmed:
26
12
2018
medline:
22
9
2020
entrez:
25
12
2018
Statut:
ppublish
Résumé
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.
Sections du résumé
BACKGROUND & AIMS
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
Collectively, miRNA modulation in hepatocytes, an easy-to-target cell type in the liver, may serve as a potential therapeutic approach for liver fibrosis.
LAY SUMMARY
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.
Identifiants
pubmed: 30582979
pii: S0168-8278(18)32635-7
doi: 10.1016/j.jhep.2018.12.016
pii:
doi:
Substances chimiques
MIRN221 microRNA, human
0
MIRN221 microRNA, mouse
0
MicroRNAs
0
Carbon Tetrachloride
CL2T97X0V0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
722-734Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.