dc.contributor.author | Simón Espinosa, Jorge | |
dc.contributor.author | Goikoetxea Usandizaga, Naroa | |
dc.contributor.author | Serrano Maciá, Marina | |
dc.contributor.author | Fernández Ramos, David | |
dc.contributor.author | Saenz de Urturi Indart, Diego | |
dc.contributor.author | Gruskos, Jessica J. | |
dc.contributor.author | Fernández Tussy, Pablo | |
dc.contributor.author | Lachiondo Ortega, Sofía | |
dc.contributor.author | González Recio, Irene | |
dc.contributor.author | Rodríguez Agudo, Rubén | |
dc.contributor.author | Gutiérrez de Juan, Virginia | |
dc.contributor.author | Rodríguez Iruretagoyena, Begoña | |
dc.contributor.author | Varela Rey, Marta | |
dc.contributor.author | Giménez Mascarell, Paula | |
dc.contributor.author | Mercado Gómez, María | |
dc.contributor.author | Gómez Santos, Beatriz | |
dc.contributor.author | Fernández Rodríguez, Carmen | |
dc.contributor.author | Lopitz Otsoa, Fernando | |
dc.contributor.author | Bizkarguenaga, Maider | |
dc.contributor.author | Dames, Sibylle | |
dc.contributor.author | Schaeper, Ute | |
dc.contributor.author | Martin, Franz | |
dc.contributor.author | Sabio, Guadalupe | |
dc.contributor.author | Iruzubieta, Paula | |
dc.contributor.author | Crespo, Javier | |
dc.contributor.author | Aspichueta Celaá, Patricia | |
dc.contributor.author | Chu, Kevan H. Y. | |
dc.contributor.author | Buccella, Daniela | |
dc.contributor.author | Martín Plágaro, César Augusto | |
dc.contributor.author | Cardoso Delgado, Teresa de Jesús | |
dc.contributor.author | Martínez de la Cruz, Alfonso | |
dc.contributor.author | Martínez Chantar, María Luz ![ORCID](/themes/Mirage2//images/orcid_16x16.png) | |
dc.date.accessioned | 2021-07-20T11:00:03Z | |
dc.date.available | 2021-07-20T11:00:03Z | |
dc.date.issued | 2021-07 | |
dc.identifier.citation | Journal Of Hepatology 75(1) : 34-45 (2021) | es_ES |
dc.identifier.issn | 0168-8278 | |
dc.identifier.issn | 1600-0641 | |
dc.identifier.uri | http://hdl.handle.net/10810/52534 | |
dc.description.abstract | Background & Aims: Perturbations of intracellular magnesium (Mg2+) homeostasis have implications for cell physiology. The cyclin M family, CNNM, perform key functions in the transport of Mg2+ across cell membranes. Herein, we aimed to elucidate the role of CNNM4 in the development of non-alcoholic steatohepatitis (NASH).
Methods: Serum Mg2+ levels and hepatic CNNM4 expression were characterised in clinical samples. Primary hepatocytes were cultured under methionine and choline deprivation. A 0.1% methionine and choline-deficient diet, or a choline-deficient high-fat diet were used to induce NASH in our in vivo rodent models. Cnnm4 was silenced using siRNA, in vitro with DharmaFECT and in vivo with Invivofectamine (R) or conjugated to N-acetylgalactosamine.
Results: Patients with NASH showed hepatic CNNM4 over-expression and dysregulated Mg2+ levels in the serum. Cnnm4 silencing ameliorated hepatic lipid accumulation, inflammation and fibrosis in the rodent NASH models. Mechanistically, CNNM4 knockdown in hepatocytes induced cellular Mg2+ accumulation, reduced endoplasmic reticulum stress, and increased microsomal triglyceride transfer activity, which promoted hepatic lipid clearance by increasing the secretion of VLDLs.
Conclusions: CNNM4 is overexpressed in patients with NASH and is responsible for dysregulated Mg2+ transport. Hepatic CNNM4 is a promising therapeutic target for the treatment of NASH.
Lay summary: Cyclin M4 (CNNM4) is overexpressed in nonalcoholic steatohepatitis (NASH) and promotes the export of magnesium from the liver. The liver-specific silencing of Cnnm4 ameliorates NASH by reducing endoplasmic reticulum stress and promoting the activity of microsomal triglyceride transfer protein. | es_ES |
dc.description.sponsorship | Ministerio de Ciencia e Innovacion, Programa Retos-Colaboracion RTC2019-007125-1 (for JS and MLM-C); Instituto de Salud Carlos III, Proyectos de Investigacion en Salud DTS20/00138 (for JS and MLM-C); Departamento de Industria del Gobierno Vasco (for MLM-C); Ministerio de Ciencia, Innovacion y Universidades MICINN: SAF2017-87301-R and RTI2018-096759-A-100 integrado en el Plan Estatal de Investigacion Cientifica y Tecnica y Innovacion, cofinanciado con Fondos FEDER (for MLM-C and TCD, respectively); BIOEF (Basque Foundation for Innovation and Health Research); EITB Maratoia BIO15/CA/014; Asociacion Espanola contra el Cancer (MLM-C, TCD); Fundacion Cientifica de la Asociacion Espanola Contra el Cancer (AECC Scientific Foundation) Rare Tumor Calls 2017 (for MLM); La Caixa Foundation Program (for MLM); Fundacion BBVA UMBRELLA project (for MLM); BFU2015-70067-REDC, BFU2016-77408-R, and BES-2017-080435 (MINECO/FEDER, UE) and the FIGHT-CNNM2 project from the EJP RD Joint Transnational Call (JTC2019) (Ref. AC19/00073) (for LAM-C); RTI2018-095134-B-100 and Grupos de Investigacion del Sistema Universitario Vasco (IT971-16) (for PA); National Institutes of Health under grant CA217817 (for DB); AGL2014-54585-R, AGL-2017-86927-R and EQC2018-004897-P from MINECO; PC0148-2016-0149 and PAI-BIO311 from Junta de Andalucia (for FM). Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III. We thank Silence Therapeutics plc. for the financial support provided. We thank MINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644) | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Elsevier | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/RTC2019-007125-1 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/SAF2017-87301-R | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/RTI2018-096759-A-100 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/BFU2015-70067-REDC | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/BFU2016-77408-R | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/BES-2017-080435 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/RTI2018-095134-B-100 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/AGL2014-54585-R | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/AGL-2017-86927-R | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/EQC2018-004897-P | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/SEV-2016-0644 | 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 | non-alcoholic steatohepatitis | es_ES |
dc.subject | NASHCyclin M4 | es_ES |
dc.subject | CNNM4 | es_ES |
dc.subject | magnesium | es_ES |
dc.subject | therapy | es_ES |
dc.subject | siRNA | es_ES |
dc.subject | endoplasmic reticulum stress | es_ES |
dc.subject | microsomal triglyceride transfer protein | es_ES |
dc.subject | MTP | es_ES |
dc.subject | ER stress | es_ES |
dc.subject | liver | es_ES |
dc.subject | disease | es_ES |
dc.subject | cancer | es_ES |
dc.subject | steatohepatitis | es_ES |
dc.subject | pathogenesis | es_ES |
dc.subject | cells | es_ES |
dc.title | Magnesium Accumulation Upon Cyclin M4 Silencing Activates Microsomal Triglyceride Transfer Protein Improving NASH | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY-NC-ND 4.0) | es_ES |
dc.rights.holder | Atribución-NoComercial-SinDerivadas 3.0 España | * |
dc.relation.publisherversion | https://www-sciencedirect-com.ehu.idm.oclc.org/science/article/pii/S0168827821000945?via%3Dihub | es_ES |
dc.identifier.doi | 10.1016/j.jhep.2021.01.043 | |
dc.departamentoes | Bioquímica y biología molecular | es_ES |
dc.departamentoes | Fisiología | es_ES |
dc.departamentoeu | Biokimika eta biologia molekularra | es_ES |
dc.departamentoeu | Fisiologia | es_ES |