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Targeting hepatic miR-221/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice

BACKGROUND: Effective targeting therapies for common chronic liver disease nonalcoholic steatohepatitis (NASH) are in urgent need. MicroRNA-targeted therapeutics would be potentially an effective treatment strategy of hepatic diseases. Here we investigated the functional role of miR-221/222 and the...

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Autores principales: Jiang, Xiuli, Jiang, Lei, Shan, Aijing, Su, Yutong, Cheng, Yulong, Song, Dalong, Ji, He, Ning, Guang, Wang, Weiqing, Cao, Yanan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284352/
https://www.ncbi.nlm.nih.gov/pubmed/30316865
http://dx.doi.org/10.1016/j.ebiom.2018.09.051
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author Jiang, Xiuli
Jiang, Lei
Shan, Aijing
Su, Yutong
Cheng, Yulong
Song, Dalong
Ji, He
Ning, Guang
Wang, Weiqing
Cao, Yanan
author_facet Jiang, Xiuli
Jiang, Lei
Shan, Aijing
Su, Yutong
Cheng, Yulong
Song, Dalong
Ji, He
Ning, Guang
Wang, Weiqing
Cao, Yanan
author_sort Jiang, Xiuli
collection PubMed
description BACKGROUND: Effective targeting therapies for common chronic liver disease nonalcoholic steatohepatitis (NASH) are in urgent need. MicroRNA-targeted therapeutics would be potentially an effective treatment strategy of hepatic diseases. Here we investigated the functional role of miR-221/222 and the therapeutic effects of antimiRs-221/222 in NASH mouse models. METHODS: We generated the miR-221/222(flox/flox) mice on a C57BL/6 J background and the hepatic miR-221/222 knockout (miR-221/222-LKO) mice. The mice were challenged with the methionine and choline deficient diet (MCDD) or chronic carbon tetrachloride (CCl(4)) treatment to generate experimental steatohepatitis models. Adenovirus-mediated re-expression of miR-221/222 was performed on the MCDD-fed miR-221/222-LKO mice. The MCDD and control diet-fed mice were treated with locked nucleic acid (LNA)-based antimiRs of miR-221/222 to evaluate the therapeutic effects. Histological analysis, RNA-seq, quantitative PCR and Western blot of liver tissues were carried out to study the hepatic lipid accumulation, inflammation and collagen deposition in mouse models. FINDINGS: Hepatic deletion of miR-221/222 resulted in significant reduction of liver fibrosis, lipid deposition and inflammatory infiltration in the MCDD-fed and CCl4-treated mouse models. The hepatic steatosis and fibrosis were dramatically aggravated by miR-221/222 re-expression in MCDD-fed miR-221/222-LKO mice. AntimiRs of miR-221/222 could effectively reduce the MCDD-mediated hepatic steatosis and fibrosis. Systematically mechanistic study revealed that hepatic miR-221/222 controlled the expression of target gene Timp3 and promoted the progression of NASH. INTERPRETATION: Our findings demonstrate that miR-221/222 are crucial for the regulation of lipid metabolism, inflammation and fibrosis in the liver. LNA-antimiRs targeted miR-221/222 could reduce steatohepatitis with prominent antifibrotic effect in NASH mice. FUND: This work is supported by the Natural Science Foundation of China (81530020, 81390352 to Dr. Ning and 81522032 to Dr. Cao and 81670793 to Dr. Jiang); National Key Research and Development Program (No. 2016YFC0905001 and 2017YFC0909703 to Dr. Cao); the Shanghai Rising-Star Program (15QA1402900 to Dr. Cao); Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20171905 to Dr. Jiang).
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spelling pubmed-62843522018-12-13 Targeting hepatic miR-221/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice Jiang, Xiuli Jiang, Lei Shan, Aijing Su, Yutong Cheng, Yulong Song, Dalong Ji, He Ning, Guang Wang, Weiqing Cao, Yanan EBioMedicine Research paper BACKGROUND: Effective targeting therapies for common chronic liver disease nonalcoholic steatohepatitis (NASH) are in urgent need. MicroRNA-targeted therapeutics would be potentially an effective treatment strategy of hepatic diseases. Here we investigated the functional role of miR-221/222 and the therapeutic effects of antimiRs-221/222 in NASH mouse models. METHODS: We generated the miR-221/222(flox/flox) mice on a C57BL/6 J background and the hepatic miR-221/222 knockout (miR-221/222-LKO) mice. The mice were challenged with the methionine and choline deficient diet (MCDD) or chronic carbon tetrachloride (CCl(4)) treatment to generate experimental steatohepatitis models. Adenovirus-mediated re-expression of miR-221/222 was performed on the MCDD-fed miR-221/222-LKO mice. The MCDD and control diet-fed mice were treated with locked nucleic acid (LNA)-based antimiRs of miR-221/222 to evaluate the therapeutic effects. Histological analysis, RNA-seq, quantitative PCR and Western blot of liver tissues were carried out to study the hepatic lipid accumulation, inflammation and collagen deposition in mouse models. FINDINGS: Hepatic deletion of miR-221/222 resulted in significant reduction of liver fibrosis, lipid deposition and inflammatory infiltration in the MCDD-fed and CCl4-treated mouse models. The hepatic steatosis and fibrosis were dramatically aggravated by miR-221/222 re-expression in MCDD-fed miR-221/222-LKO mice. AntimiRs of miR-221/222 could effectively reduce the MCDD-mediated hepatic steatosis and fibrosis. Systematically mechanistic study revealed that hepatic miR-221/222 controlled the expression of target gene Timp3 and promoted the progression of NASH. INTERPRETATION: Our findings demonstrate that miR-221/222 are crucial for the regulation of lipid metabolism, inflammation and fibrosis in the liver. LNA-antimiRs targeted miR-221/222 could reduce steatohepatitis with prominent antifibrotic effect in NASH mice. FUND: This work is supported by the Natural Science Foundation of China (81530020, 81390352 to Dr. Ning and 81522032 to Dr. Cao and 81670793 to Dr. Jiang); National Key Research and Development Program (No. 2016YFC0905001 and 2017YFC0909703 to Dr. Cao); the Shanghai Rising-Star Program (15QA1402900 to Dr. Cao); Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20171905 to Dr. Jiang). Elsevier 2018-10-10 /pmc/articles/PMC6284352/ /pubmed/30316865 http://dx.doi.org/10.1016/j.ebiom.2018.09.051 Text en © 2018 Published by Elsevier B.V. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research paper
Jiang, Xiuli
Jiang, Lei
Shan, Aijing
Su, Yutong
Cheng, Yulong
Song, Dalong
Ji, He
Ning, Guang
Wang, Weiqing
Cao, Yanan
Targeting hepatic miR-221/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice
title Targeting hepatic miR-221/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice
title_full Targeting hepatic miR-221/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice
title_fullStr Targeting hepatic miR-221/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice
title_full_unstemmed Targeting hepatic miR-221/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice
title_short Targeting hepatic miR-221/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice
title_sort targeting hepatic mir-221/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice
topic Research paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284352/
https://www.ncbi.nlm.nih.gov/pubmed/30316865
http://dx.doi.org/10.1016/j.ebiom.2018.09.051
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