miR-873-5p targets mitochondrial GNMT-Complex II interface contributing to non-alcoholic fatty liver disease
dc.contributor.author | Fernández Tussy, Pablo | |
dc.contributor.author | Fernández Ramos, David | |
dc.contributor.author | Lopitz Otsoa, Fernando | |
dc.contributor.author | Simon, Jorge | |
dc.contributor.author | Barbier Torres, Lucía | |
dc.contributor.author | Gómez Santos, Beatriz | |
dc.contributor.author | Nuñez García, Maitane | |
dc.contributor.author | Azkargorta, Mikel | |
dc.contributor.author | Serrano Maciá, Marina | |
dc.contributor.author | Gutiérrez de Juan, Virginia | |
dc.contributor.author | Serrano Maciá, Marina | |
dc.contributor.author | Rodríguez Agudo, Rubén | |
dc.contributor.author | Iruzubieta, Paula | |
dc.contributor.author | Anguita Castillo, Juan de Dios | |
dc.contributor.author | Castro, Rui E. | |
dc.contributor.author | Champagne, Devin | |
dc.contributor.author | Rincon, Mercedes | |
dc.contributor.author | Elortza, Felix | |
dc.contributor.author | Arslanow, Anita | |
dc.contributor.author | Krawczyk, Marcin | |
dc.contributor.author | Lammert, Frank | |
dc.contributor.author | Kirchmeyer, Melanie | |
dc.contributor.author | Behrmann, Iris | |
dc.contributor.author | Crespo, Javier | |
dc.contributor.author | Lu, Shelly C. | |
dc.contributor.author | Mato, José M. | |
dc.contributor.author | Varela Rey, Marta | |
dc.contributor.author | Aspichueta Celaá, Patricia | |
dc.contributor.author | Delgado, Teresa C. | |
dc.contributor.author | Martínez Chantar, María Luz | |
dc.date.accessioned | 2020-01-29T09:33:55Z | |
dc.date.available | 2020-01-29T09:33:55Z | |
dc.date.issued | 2019-08-16 | |
dc.identifier.citation | Molecular Metabolism 29 : 40-54 (2019) | es_ES |
dc.identifier.issn | 2212-8778 | |
dc.identifier.uri | http://hdl.handle.net/10810/39225 | |
dc.description.abstract | Objective: Non-alcoholic fatly liver disease (NAFLD) is a complex pathology in which several dysfunctions, including alterations in metabolic pathways, mitochondrial functionality and unbalanced lipid import/export, lead to lipid accumulation and progression to inflammation and fibrosis. The enzyme glycine N-methyltransferase (GNMT), the most important enzyme implicated in S-adenosylmethionine catabolism in the liver, is downregulated during NAFLD progression. We have studied the mechanism involved in GNMT downregulation by its repressor microRNA miR-873-5p and the metabolic pathways affected in NAFLD as well as the benefit of recovery GNMT expression. Methods: miR-873-5p and GNMT expression were evaluated in liver biopsies of NAFLD/NASH patients. Different in vitro and in vivo NAFLD murine models were used to assess miR-873-5p/GNMT involvement in fatty liver progression through targeting of the miR-873-5p as NAFLD therapy. Results: We describe a new function of GNMT as an essential regulator of Complex II activity in the electron transport chain in the mitochondria. In NAFLD, GNMT expression is controlled by miR-873-5p in the hepatocytes, leading to disruptions in mitochondria! functionality in a preclinical murine non-alcoholic steatohepatitis (NASH) model. Upregulation of miR-873-5p is shown in the liver of NAFLD/NASH patients, correlating with hepatic GNMT depletion. Importantly, NASH therapies based on anti-miR-873-5p resolve lipid accumulation, inflammation and fibrosis by enhancing fatty acid beta-oxidation in the mitochondria. Therefore, miR-873-5p inhibitor emerges as a potential tool for NASH treatment. Conclusion: GNMT participates in the regulation of metabolic pathways and mitochondria! functionality through the regulation of Complex II activity in the electron transport chain. In NAFLD, GNMT is repressed by miR-873-5p and its targeting arises as a valuable therapeutic option for treatment. (C) 2019 The Authors. Published by Elsevier GmbH. | es_ES |
dc.description.sponsorship | This work was supported by grants from NIH (US Department of Health and Human services)-R01AT001576 (to S.C.L., J.M.M., and M.L.M.-C.), Ministerio de Economia, Industria y Competitividad: SAF2017-87301-R (to M.L.M.-C.), SAF2015-64352-R (to P.A.), Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C.), Gobierno Vasco-Departamento de Educacion IT-336-10 (to PA), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD (M.L.M.-C.), ELKARTEK 2016, Departamento de Industria del Gobierno Vasco (to M.L.M.-C), Asociacion Espanola contra el Cancer (to T.C.D., P.F.-T. and M.L.M.-C.), Mitotherapeutix (to M.L.M.-C.), Daniel Alagille award from EASL (to T.C.D), Fundacion Cientifica de la Asociacion Espanola Contra el Cancer (AECC Scientific Foundation) Rare Tumor Calls 2017 (to M.L.M.-C.), La Caixa Foundation Program (to M.L.M.-C.), Ayudas Fundacion BBVA a Equipos de Investigacion Cientifica 2019 (to M.L.M.-C.). Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III. We thank this work produced with the support of a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (to M.V.R.). This work was supported by Fonds National de la Recherche Luxembourg and the Deutsche Forschungsgemeinschaft (C12/BM/3975937, FL/997/7-1, Inter "HepmiRSTAT", to I.B. and F.L.). We thank MINECO for the Severo Ochoa Excellence Accreditation (SEV2016-0644). | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Elsevier | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/SAF2017-87301-R | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/SAF2015-64352-R | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/SEV2016-0644 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/es/ | * |
dc.subject | nash | es_ES |
dc.subject | gnmt | es_ES |
dc.subject | mitochondria | es_ES |
dc.subject | beta-oxidation | es_ES |
dc.subject | metabolism | es_ES |
dc.subject | microrna | es_ES |
dc.subject | glycine-n-methyltransferase | es_ES |
dc.subject | hepatocellular-carcinoma | es_ES |
dc.subject | gene-expression | es_ES |
dc.subject | steatohepatitis | es_ES |
dc.subject | steatosis | es_ES |
dc.subject | phosphatidylethanolamine | es_ES |
dc.subject | neddylation | es_ES |
dc.subject | dysfunction | es_ES |
dc.subject | lipogenesis | es_ES |
dc.subject | metabolism | es_ES |
dc.title | miR-873-5p targets mitochondrial GNMT-Complex II interface contributing to non-alcoholic fatty liver disease | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | © 2019 The Authors. Published by Elsevier GmbH. This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed. | es_ES |
dc.rights.holder | Atribución-NoComercial-SinDerivadas 3.0 España | * |
dc.relation.publisherversion | https://www.sciencedirect.com/science/article/pii/S2212877819306209?via%3Dihub | es_ES |
dc.departamentoes | Fisiología | es_ES |
dc.departamentoeu | Fisiologia | es_ES |
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Except where otherwise noted, this item's license is described as © 2019 The Authors. Published by Elsevier GmbH. This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.