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MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis

Glycine N-methyltransferase (GNMT) is the most abundant methyltransferase in the liver and a master regulator of the transmethylation flux. GNMT downregulation leads to loss of liver function progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Moreover, GNMT deficiency aggravates chole...

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Autores principales: Fernández-Ramos, David, Fernández-Tussy, Pablo, Lopitz-Otsoa, Fernando, Gutiérrez-de-Juan, Virginia, Navasa, Nicolás, Barbier-Torres, Lucía, Zubiete-Franco, Imanol, Simón, Jorge, Fernández, Agustín F., Arbelaiz, Ander, Aransay, Ana M., Lavín, José Luis, Beraza, Naiara, Perugorria, María J., Banales, Jesus M., Villa, Erica, Fraga, Mario F., Anguita, Juan, Avila, Matias A., Berasain, Carmen, Iruzibieta, Paula, Crespo, Javier, Lu, Shelly C., Varela-Rey, Marta, Mato, José M., Delgado, Teresa C., Martínez-Chantar, María L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148053/
https://www.ncbi.nlm.nih.gov/pubmed/30237481
http://dx.doi.org/10.1038/s41419-018-1014-y
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author Fernández-Ramos, David
Fernández-Tussy, Pablo
Lopitz-Otsoa, Fernando
Gutiérrez-de-Juan, Virginia
Navasa, Nicolás
Barbier-Torres, Lucía
Zubiete-Franco, Imanol
Simón, Jorge
Fernández, Agustín F.
Arbelaiz, Ander
Aransay, Ana M.
Lavín, José Luis
Beraza, Naiara
Perugorria, María J.
Banales, Jesus M.
Villa, Erica
Fraga, Mario F.
Anguita, Juan
Avila, Matias A.
Berasain, Carmen
Iruzibieta, Paula
Crespo, Javier
Lu, Shelly C.
Varela-Rey, Marta
Mato, José M.
Delgado, Teresa C.
Martínez-Chantar, María L.
author_facet Fernández-Ramos, David
Fernández-Tussy, Pablo
Lopitz-Otsoa, Fernando
Gutiérrez-de-Juan, Virginia
Navasa, Nicolás
Barbier-Torres, Lucía
Zubiete-Franco, Imanol
Simón, Jorge
Fernández, Agustín F.
Arbelaiz, Ander
Aransay, Ana M.
Lavín, José Luis
Beraza, Naiara
Perugorria, María J.
Banales, Jesus M.
Villa, Erica
Fraga, Mario F.
Anguita, Juan
Avila, Matias A.
Berasain, Carmen
Iruzibieta, Paula
Crespo, Javier
Lu, Shelly C.
Varela-Rey, Marta
Mato, José M.
Delgado, Teresa C.
Martínez-Chantar, María L.
author_sort Fernández-Ramos, David
collection PubMed
description Glycine N-methyltransferase (GNMT) is the most abundant methyltransferase in the liver and a master regulator of the transmethylation flux. GNMT downregulation leads to loss of liver function progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Moreover, GNMT deficiency aggravates cholestasis-induced fibrogenesis. To date, little is known about the mechanisms underlying downregulation of GNMT levels in hepatic fibrosis and cirrhosis. On this basis, microRNAs are epigenetic regulatory elements that play important roles in liver pathology. In this work, we aim to study the regulation of GNMT by microRNAs during liver fibrosis and cirrhosis. Luciferase assay on the 3ʹUTR-Gnmt was used to confirm in silico analysis showing that GNMT is potentially targeted by the microRNA miR-873-5p. Correlation between GNMT and miR-873-5p in human cholestasis and cirrhosis together with miR-873-5p inhibition in vivo in different mouse models of liver cholestasis and fibrosis [bile duct ligation and Mdr2 (Abcb4)(-/-) mouse] were then assessed. The analysis of liver tissue from cirrhotic and cholestatic patients, as well as from the animal models, showed that miR-873-5p inversely correlated with the expression of GNMT. Importantly, high circulating miR-873-5p was also detected in cholestastic and cirrhotic patients. Preclinical studies with anti-miR-873-5p treatment in bile duct ligation and Mdr2(-/-) mice recovered GNMT levels in association with ameliorated inflammation and fibrosis mainly by counteracting hepatocyte apoptosis and cholangiocyte proliferation. In conclusion, miR-873-5p emerges as a novel marker for liver fibrosis, cholestasis, and cirrhosis and therapeutic approaches based on anti-miR-873-5p may be effective treatments for liver fibrosis and cholestatic liver disease.
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spelling pubmed-61480532018-09-25 MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis Fernández-Ramos, David Fernández-Tussy, Pablo Lopitz-Otsoa, Fernando Gutiérrez-de-Juan, Virginia Navasa, Nicolás Barbier-Torres, Lucía Zubiete-Franco, Imanol Simón, Jorge Fernández, Agustín F. Arbelaiz, Ander Aransay, Ana M. Lavín, José Luis Beraza, Naiara Perugorria, María J. Banales, Jesus M. Villa, Erica Fraga, Mario F. Anguita, Juan Avila, Matias A. Berasain, Carmen Iruzibieta, Paula Crespo, Javier Lu, Shelly C. Varela-Rey, Marta Mato, José M. Delgado, Teresa C. Martínez-Chantar, María L. Cell Death Dis Article Glycine N-methyltransferase (GNMT) is the most abundant methyltransferase in the liver and a master regulator of the transmethylation flux. GNMT downregulation leads to loss of liver function progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Moreover, GNMT deficiency aggravates cholestasis-induced fibrogenesis. To date, little is known about the mechanisms underlying downregulation of GNMT levels in hepatic fibrosis and cirrhosis. On this basis, microRNAs are epigenetic regulatory elements that play important roles in liver pathology. In this work, we aim to study the regulation of GNMT by microRNAs during liver fibrosis and cirrhosis. Luciferase assay on the 3ʹUTR-Gnmt was used to confirm in silico analysis showing that GNMT is potentially targeted by the microRNA miR-873-5p. Correlation between GNMT and miR-873-5p in human cholestasis and cirrhosis together with miR-873-5p inhibition in vivo in different mouse models of liver cholestasis and fibrosis [bile duct ligation and Mdr2 (Abcb4)(-/-) mouse] were then assessed. The analysis of liver tissue from cirrhotic and cholestatic patients, as well as from the animal models, showed that miR-873-5p inversely correlated with the expression of GNMT. Importantly, high circulating miR-873-5p was also detected in cholestastic and cirrhotic patients. Preclinical studies with anti-miR-873-5p treatment in bile duct ligation and Mdr2(-/-) mice recovered GNMT levels in association with ameliorated inflammation and fibrosis mainly by counteracting hepatocyte apoptosis and cholangiocyte proliferation. In conclusion, miR-873-5p emerges as a novel marker for liver fibrosis, cholestasis, and cirrhosis and therapeutic approaches based on anti-miR-873-5p may be effective treatments for liver fibrosis and cholestatic liver disease. Nature Publishing Group UK 2018-09-20 /pmc/articles/PMC6148053/ /pubmed/30237481 http://dx.doi.org/10.1038/s41419-018-1014-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Fernández-Ramos, David
Fernández-Tussy, Pablo
Lopitz-Otsoa, Fernando
Gutiérrez-de-Juan, Virginia
Navasa, Nicolás
Barbier-Torres, Lucía
Zubiete-Franco, Imanol
Simón, Jorge
Fernández, Agustín F.
Arbelaiz, Ander
Aransay, Ana M.
Lavín, José Luis
Beraza, Naiara
Perugorria, María J.
Banales, Jesus M.
Villa, Erica
Fraga, Mario F.
Anguita, Juan
Avila, Matias A.
Berasain, Carmen
Iruzibieta, Paula
Crespo, Javier
Lu, Shelly C.
Varela-Rey, Marta
Mato, José M.
Delgado, Teresa C.
Martínez-Chantar, María L.
MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis
title MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis
title_full MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis
title_fullStr MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis
title_full_unstemmed MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis
title_short MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis
title_sort mir-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148053/
https://www.ncbi.nlm.nih.gov/pubmed/30237481
http://dx.doi.org/10.1038/s41419-018-1014-y
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