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Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis

Osteopontin (OPN) promotes hepatic fibrosis, and developing therapies targeting OPN expression in settings of hepatic injury holds promise. The polyphenol epigallocatechin-3-gallate (EGCG), found in high concentrations in green tea, downregulates OPN expression through OPN mRNA degradation, but the...

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Autores principales: Arffa, M. L., Zapf, M. A., Kothari, A. N., Chang, V., Gupta, G. N., Ding, X., Al-Gayyar, M. M., Syn, W., Elsherbiny, N. M., Kuo, P. C., Mi, Z.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147893/
https://www.ncbi.nlm.nih.gov/pubmed/27935974
http://dx.doi.org/10.1371/journal.pone.0167435
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author Arffa, M. L.
Zapf, M. A.
Kothari, A. N.
Chang, V.
Gupta, G. N.
Ding, X.
Al-Gayyar, M. M.
Syn, W.
Elsherbiny, N. M.
Kuo, P. C.
Mi, Z.
author_facet Arffa, M. L.
Zapf, M. A.
Kothari, A. N.
Chang, V.
Gupta, G. N.
Ding, X.
Al-Gayyar, M. M.
Syn, W.
Elsherbiny, N. M.
Kuo, P. C.
Mi, Z.
author_sort Arffa, M. L.
collection PubMed
description Osteopontin (OPN) promotes hepatic fibrosis, and developing therapies targeting OPN expression in settings of hepatic injury holds promise. The polyphenol epigallocatechin-3-gallate (EGCG), found in high concentrations in green tea, downregulates OPN expression through OPN mRNA degradation, but the mechanism is unknown. Previous work has shown that microRNAs can decrease OPN mRNA levels, and other studies have shown that EGCG modulates the expression of multiple microRNAs. In our study, we first demonstrated that OPN induces hepatic stellate cells to transform into an activated state. We then identified three microRNAs which target OPN mRNA: miR-181a, miR-10b, and miR-221. In vitro results show that EGCG upregulates all three microRNAs, and all three microRNAs are capable of down regulating OPN mRNA when administered alone. Interestingly, only miR-221 is necessary for EGCG-mediated OPN mRNA degradation and miR-221 inhibition reduces the effects of EGCG on cell function. In vivo experiments show that thioacetamide (TAA)-induced cell cytotoxicity upregulates OPN expression; treatment with EGCG blocks the effects of TAA. Furthermore, chronic treatment of EGCG in vivo upregulates all three microRNAs equally, suggesting that in more chronic treatment all three microRNAs are involved in modulating OPN expression. We conclude that in in vitro and in vivo models of TAA-induced hepatic fibrosis, EGCG inhibits OPN-dependent injury and fibrosis. EGCG works primarily by upregulating miR-221 to accelerate OPN degradation. EGCG may therefore have utility as a protective agent in settings of liver injury.
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spelling pubmed-51478932016-12-28 Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis Arffa, M. L. Zapf, M. A. Kothari, A. N. Chang, V. Gupta, G. N. Ding, X. Al-Gayyar, M. M. Syn, W. Elsherbiny, N. M. Kuo, P. C. Mi, Z. PLoS One Research Article Osteopontin (OPN) promotes hepatic fibrosis, and developing therapies targeting OPN expression in settings of hepatic injury holds promise. The polyphenol epigallocatechin-3-gallate (EGCG), found in high concentrations in green tea, downregulates OPN expression through OPN mRNA degradation, but the mechanism is unknown. Previous work has shown that microRNAs can decrease OPN mRNA levels, and other studies have shown that EGCG modulates the expression of multiple microRNAs. In our study, we first demonstrated that OPN induces hepatic stellate cells to transform into an activated state. We then identified three microRNAs which target OPN mRNA: miR-181a, miR-10b, and miR-221. In vitro results show that EGCG upregulates all three microRNAs, and all three microRNAs are capable of down regulating OPN mRNA when administered alone. Interestingly, only miR-221 is necessary for EGCG-mediated OPN mRNA degradation and miR-221 inhibition reduces the effects of EGCG on cell function. In vivo experiments show that thioacetamide (TAA)-induced cell cytotoxicity upregulates OPN expression; treatment with EGCG blocks the effects of TAA. Furthermore, chronic treatment of EGCG in vivo upregulates all three microRNAs equally, suggesting that in more chronic treatment all three microRNAs are involved in modulating OPN expression. We conclude that in in vitro and in vivo models of TAA-induced hepatic fibrosis, EGCG inhibits OPN-dependent injury and fibrosis. EGCG works primarily by upregulating miR-221 to accelerate OPN degradation. EGCG may therefore have utility as a protective agent in settings of liver injury. Public Library of Science 2016-12-09 /pmc/articles/PMC5147893/ /pubmed/27935974 http://dx.doi.org/10.1371/journal.pone.0167435 Text en © 2016 Arffa et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Arffa, M. L.
Zapf, M. A.
Kothari, A. N.
Chang, V.
Gupta, G. N.
Ding, X.
Al-Gayyar, M. M.
Syn, W.
Elsherbiny, N. M.
Kuo, P. C.
Mi, Z.
Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis
title Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis
title_full Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis
title_fullStr Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis
title_full_unstemmed Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis
title_short Epigallocatechin-3-Gallate Upregulates miR-221 to Inhibit Osteopontin-Dependent Hepatic Fibrosis
title_sort epigallocatechin-3-gallate upregulates mir-221 to inhibit osteopontin-dependent hepatic fibrosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147893/
https://www.ncbi.nlm.nih.gov/pubmed/27935974
http://dx.doi.org/10.1371/journal.pone.0167435
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