Silencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation
dc.contributor.author | Barbier Torres, Lucía | |
dc.contributor.author | Fortner, Karen A. | |
dc.contributor.author | Iruzubieta, Paula | |
dc.contributor.author | Delgado, Teresa C. | |
dc.contributor.author | Giddings, Emily | |
dc.contributor.author | Chen, Youdinghuan | |
dc.contributor.author | Champagne, Devin | |
dc.contributor.author | Fernández Ramos, David | |
dc.contributor.author | Mestre, Daniela | |
dc.contributor.author | Gómez Santos, Beatriz | |
dc.contributor.author | Varela Rey, Marta | |
dc.contributor.author | Gutiérrez de Juan, Virginia | |
dc.contributor.author | Fernández Tussy, Pablo | |
dc.contributor.author | Zubiete Franco, Imanol | |
dc.contributor.author | García Monzón, Carmelo | |
dc.contributor.author | González Rodríguez, Águeda | |
dc.contributor.author | Oza, Dhaval | |
dc.contributor.author | Valença Pereira, Felipe | |
dc.contributor.author | Fang, Qian | |
dc.contributor.author | Crespo, Javier | |
dc.contributor.author | Aspichueta Celaá, Patricia | |
dc.contributor.author | Tremblay, Frederic | |
dc.contributor.author | Christensen, Brock C. | |
dc.contributor.author | Anguita Castillo, Juan de Dios | |
dc.contributor.author | Martínez Chantar, María Luz ![]() | |
dc.contributor.author | Rincón, Mercedes | |
dc.date.accessioned | 2020-10-20T10:20:05Z | |
dc.date.available | 2020-10-20T10:20:05Z | |
dc.date.issued | 2020-07-03 | |
dc.identifier.citation | Nature Communications 11 : (2020) // Article ID 3360 | es_ES |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | http://hdl.handle.net/10810/47048 | |
dc.description.abstract | Nonalcoholic fatty liver disease (NAFLD) is considered the next major health epidemic with an estimated 25% worldwide prevalence. No drugs have yet been approved and NAFLD remains a major unmet need. Here, we identify MCJ (Methylation-Controlled J protein) as a target for non-alcoholic steatohepatitis (NASH), an advanced phase of NAFLD. MCJ is an endogenous negative regulator of the respiratory chain Complex I that acts to restrain mitochondrial respiration. We show that therapeutic targeting of MCJ in the liver with nanoparticle- and GalNAc-formulated siRNA efficiently reduces liver lipid accumulation and fibrosis in multiple NASH mouse models. Decreasing MCJ expression enhances the capacity of hepatocytes to mediate beta -oxidation of fatty acids and minimizes lipid accumulation, which results in reduced hepatocyte damage and fibrosis. Moreover, MCJ levels in the liver of NAFLD patients are elevated relative to healthy subjects. Thus, inhibition of MCJ emerges as an alternative approach to treat NAFLD. Non-alcoholic fatty liver (NAFLD) disease causes degeneration of the liver, affects about 25% of people globally, and has no approved treatment. Here, the authors show that the therapeutic siRNA-driven silencing of MCJ in the liver is an effective and safe treatment for NAFLD in multiple mouse models. | es_ES |
dc.description.sponsorship | We thank Douglas Taatjes and Nicole Bouffard for help with confocal microscopy analysis (Microscopy Imaging Center) at the University of Vermont. We also thank the University of Vermont Medical Center's Department of Pathology and Laboratory Medicine Histology and Clinical Laboratories for assistance with liver section staining and AST/ALT measurement, respectively. This work was supported by NIH STTR R41DK112429 (M.R.), NIH PO GM103496 (M.R.), Mitotherapeutix LLC (M.R., K.F, and M.L.M.-C.), MINECO/Feder SAF2015-65327-R and RTI2018-096494-B-100 (J.A.), MINECO/Feder SAF2017-87301-R (M.L.M-C.), BIOEF (M.L.M.-C.), EITB Maratoia BIO15/CA/014 (M.L.M-C), BBVA (M.L.M.-C.), La Caixa Foundation (M.L.M.-C.), Basque Country Health Department 2013111114 (M.L.M-C), MINECO/Feder SAF2015-64352-R (P.A.) and MINECO-Feder RTI2018-095134-B-100 (P.A.). ISCIII-Feder PI17/00535 (C.G.-M.), ISCIII-Feder CP14/00181, and PI16/00823 (A.G-R.), and Francisco Cobos Foundation (A.G.-R.). CIC bioGUNE is the recipient of a Severo Ochoa Excellence Accreditation (SEV-2016-0644) by the Ministry of Science, Innovation and Universities. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Nature | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/SAF2015-65327-R | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/RTI2018-096494-B-100 | 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/RTI2018-095134-B-100 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.subject | respiratory-chain | es_ES |
dc.subject | DNA methylation | es_ES |
dc.subject | obesity | es_ES |
dc.subject | delivery | es_ES |
dc.subject | pathogenesis | es_ES |
dc.subject | therapies | es_ES |
dc.subject | repressor | es_ES |
dc.subject | model | es_ES |
dc.subject | gene | es_ES |
dc.subject | nash | es_ES |
dc.title | Silencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | 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/. | es_ES |
dc.rights.holder | Atribución 3.0 España | * |
dc.relation.publisherversion | https://www.nature.com/articles/s41467-020-16991-2 | es_ES |
dc.identifier.doi | 10.1038/s41467-020-16991-2 | |
dc.departamentoes | Fisiología | es_ES |
dc.departamentoeu | Fisiologia | es_ES |
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