Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice

Cholestasis is a condition that leads to chronic hepatobiliary inflammation, fibrosis, and eventually cirrhosis. Many microRNAs (miRs) are known to play a role in fibrosis progression; however, the role of miR-21 during cholestasis remains unknown. Therefore, the aim of this study was to elucidate t...

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Main Authors:	Kennedy, Lindsey, Meng, Fanyin, Venter, Julie, Zhou, Tianhao, Karstens, Walker, Hargrove, Laura, Wu, Nan, Kyritsi, Konstantina, Greene, John, Invernizzi, Pietro, Bernuzzi, Francesca, Glaser, Shannon, Francis, Heather, Alpini, Gianfranco
Format:	Online
Language:	English
Published:	2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121007/

id	pubmed-5121007
recordtype	oai_dc
spelling	pubmed-51210072017-04-24 Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice Kennedy, Lindsey Meng, Fanyin Venter, Julie Zhou, Tianhao Karstens, Walker Hargrove, Laura Wu, Nan Kyritsi, Konstantina Greene, John Invernizzi, Pietro Bernuzzi, Francesca Glaser, Shannon Francis, Heather Alpini, Gianfranco Article Cholestasis is a condition that leads to chronic hepatobiliary inflammation, fibrosis, and eventually cirrhosis. Many microRNAs (miRs) are known to play a role in fibrosis progression; however, the role of miR-21 during cholestasis remains unknown. Therefore, the aim of this study was to elucidate the role of miR-21 during cholestasis-induced biliary hyperplasia and hepatic fibrosis. Wild-type (WT) and miR21−/− mice underwent sham or bile duct ligation (BDL) for 1 wk, before evaluating liver histology, biliary proliferation, hepatic stellate cell (HSC) activation, fibrotic response, and Smad-7 expression. In vitro, immortalized murine biliary cell lines (IMCL) and human hepatic stellate cell line (hHSC) were treated with either miR-21 inhibitor or control before analyzing proliferation, apoptosis, and fibrotic responses. In vivo, the levels of miR-21 were increased in total liver and cholangiocytes after BDL, and loss of miR-21 decreased the amount of BDL-induced biliary proliferation and intrahepatic biliary mass. Also, loss of miR-21 decreased BDL-induced HSC activation, collagen deposition, and expression of the fibrotic markers TGF-β1 and α-SMA. In vitro, IMCL and hHSCs treated with miR-21 inhibitor displayed decreased proliferation and expression of fibrotic markers and enhanced apoptosis when compared to control treated cells. Furthermore, mice lacking miR-21 show increased Smad-7 expression, which may be driving the decrease in biliary hyperplasia and hepatic fibrosis. During cholestatic injury miR-21 is increased and leads to increased biliary proliferation and hepatic fibrosis. Local modulation of miR-21 may be a therapeutic option for patients with cholestasis. 2016-10-24 2016-12 /pmc/articles/PMC5121007/ /pubmed/27775690 http://dx.doi.org/10.1038/labinvest.2016.112 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Kennedy, Lindsey Meng, Fanyin Venter, Julie Zhou, Tianhao Karstens, Walker Hargrove, Laura Wu, Nan Kyritsi, Konstantina Greene, John Invernizzi, Pietro Bernuzzi, Francesca Glaser, Shannon Francis, Heather Alpini, Gianfranco
spellingShingle	Kennedy, Lindsey Meng, Fanyin Venter, Julie Zhou, Tianhao Karstens, Walker Hargrove, Laura Wu, Nan Kyritsi, Konstantina Greene, John Invernizzi, Pietro Bernuzzi, Francesca Glaser, Shannon Francis, Heather Alpini, Gianfranco Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice
author_facet	Kennedy, Lindsey Meng, Fanyin Venter, Julie Zhou, Tianhao Karstens, Walker Hargrove, Laura Wu, Nan Kyritsi, Konstantina Greene, John Invernizzi, Pietro Bernuzzi, Francesca Glaser, Shannon Francis, Heather Alpini, Gianfranco
author_sort	Kennedy, Lindsey
title	Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice
title_short	Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice
title_full	Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice
title_fullStr	Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice
title_full_unstemmed	Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice
title_sort	knockout of microrna-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice
description	Cholestasis is a condition that leads to chronic hepatobiliary inflammation, fibrosis, and eventually cirrhosis. Many microRNAs (miRs) are known to play a role in fibrosis progression; however, the role of miR-21 during cholestasis remains unknown. Therefore, the aim of this study was to elucidate the role of miR-21 during cholestasis-induced biliary hyperplasia and hepatic fibrosis. Wild-type (WT) and miR21−/− mice underwent sham or bile duct ligation (BDL) for 1 wk, before evaluating liver histology, biliary proliferation, hepatic stellate cell (HSC) activation, fibrotic response, and Smad-7 expression. In vitro, immortalized murine biliary cell lines (IMCL) and human hepatic stellate cell line (hHSC) were treated with either miR-21 inhibitor or control before analyzing proliferation, apoptosis, and fibrotic responses. In vivo, the levels of miR-21 were increased in total liver and cholangiocytes after BDL, and loss of miR-21 decreased the amount of BDL-induced biliary proliferation and intrahepatic biliary mass. Also, loss of miR-21 decreased BDL-induced HSC activation, collagen deposition, and expression of the fibrotic markers TGF-β1 and α-SMA. In vitro, IMCL and hHSCs treated with miR-21 inhibitor displayed decreased proliferation and expression of fibrotic markers and enhanced apoptosis when compared to control treated cells. Furthermore, mice lacking miR-21 show increased Smad-7 expression, which may be driving the decrease in biliary hyperplasia and hepatic fibrosis. During cholestatic injury miR-21 is increased and leads to increased biliary proliferation and hepatic fibrosis. Local modulation of miR-21 may be a therapeutic option for patients with cholestasis.
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121007/
_version_	1613738811215314944

Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice

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