Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen.

Fecha de publicación: 30/04/2022 Fecha Ahead of Print: 30/04/2022

Autores de IIS La Fe

Petar Dianov Petrov

Autor
José Vicente Castell Ripoll

Autor
Ramiro Jover Atienza

Autor

Participantes ajenos a IIS La Fe

Rodríguez-Agudo R
Goikoetxea-Usandizaga N
Serrano-Maciá M
Fernández-Tussy P
Fernández-Ramos D
Lachiondo-Ortega S
González-Recio I
Gil-Pitarch C
Mercado-Gómez M
Morán L
Bizkarguenaga M
Lopitz-Otsoa F
Bravo M
Van Liempd SM
Falcon-Perez JM
Zabala-Letona A
Carracedo A
Martínez-Cruz LA
Delgado TC
Cubero FJ
Lucena MI
Andrade RJ
Mabe J
Simón J
Martínez-Chantar ML

Grupos

Hepatología experimental y Trasplante hepático

Investigador Principal

Laia Tolosa Pardo
Unidad Mixta de Investigación en Hepatología Experimental

Investigador Principal

Ramiro Jover Atienza

Abstract

Drug-induced liver injury (DILI) development is commonly associated with acetaminophen (APAP) overdose, where glutathione scavenging leads to mitochondrial dysfunction and hepatocyte death. DILI is a severe disorder without effective late-stage treatment, since N-acetyl cysteine must be administered 8 h after overdose to be efficient. Ammonia homeostasis is altered during liver diseases and, during DILI, it is accompanied by decreased glycine N-methyltransferase (GNMT) expression and S-adenosylmethionine (AdoMet) levels that suggest a reduced methionine cycle. Anti-miR-873-5p treatment prevents cell death in primary hepatocytes and the appearance of necrotic areas in liver from APAP-administered mice. In our study, we demonstrate a GNMT and methionine cycle activity restoration by the anti-miR-873-5p that reduces mitochondrial dysfunction and oxidative stress. The lack of hyperammoniemia caused by the therapy results in a decreased urea cycle, enhancing the synthesis of polyamines from ornithine and AdoMet and thus impacting the observed recovery of mitochondria and hepatocyte proliferation for regeneration. In summary, anti-miR-873-5p appears to be an effective therapy against APAP-induced liver injury, where the restoration of GNMT and the methionine cycle may prevent mitochondrial dysfunction while activating hepatocyte proliferative response.

Datos de la publicación

ISSN/ISSNe:: 2076-3921, 2076-3921
Tipo:: Article
Páginas:: -
DOI:: 10.3390/antiox11050897
Factor de Impacto:: 1,008 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

Rodríguez-Agudo R:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
Goikoetxea-Usandizaga N:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
Serrano-Maciá M:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
Fernández-Tussy P:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
Fernández-Ramos D:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain

Precision Medicine and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
Lachiondo-Ortega S:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
González-Recio I:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
Gil-Pitarch C:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
Mercado-Gómez M:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
Morán L:: Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), 28040 Madrid, Spain
Bizkarguenaga M:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain

Precision Medicine and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
Lopitz-Otsoa F:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain

Precision Medicine and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
Petrov P:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain

Instituto de Investigación. Unidad de Hepatología Experimental, Health Research Institute Hospital La Fe, Av. Fernando Abril Martorell, 46026 Valencia, Spain

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Av. de Blasco Ibáñez 15, 46010 Valencia, Spain
Bravo M:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
Van Liempd SM:: Metabolomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
Falcon-Perez JM:: Metabolomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain

IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain
Zabala-Letona A:: Cancer Cell Signaling and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain

Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Carlos III, 28029 Madrid, Spain
Carracedo A:: IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain

Cancer Cell Signaling and Metabolism Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain

Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Carlos III, 28029 Madrid, Spain

Traslational prostate cancer Research Lab, CIC bioGUNE-Basurto, Biocruces Bizkaia Research Health Institute, 48903 Barakaldo, Spain
Castell JV:: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain

Instituto de Investigación. Unidad de Hepatología Experimental, Health Research Institute Hospital La Fe, Av. Fernando Abril Martorell, 46026 Valencia, Spain

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Av. de Blasco Ibáñez 15, 46010 Valencia, Spain
Jover R:: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain

Instituto de Investigación. Unidad de Hepatología Experimental, Health Research Institute Hospital La Fe, Av. Fernando Abril Martorell, 46026 Valencia, Spain

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Av. de Blasco Ibáñez 15, 46010 Valencia, Spain
Martínez-Cruz LA:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
Delgado TC:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain
Cubero FJ:: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain

Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañon (IiSGM), 28040 Madrid, Spain
Lucena MI:: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain

Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29010 Malaga, Spain

UICEC IBIMA, Plataforma ISCiii de Investigación Clínica, 28020 Madrid, Spain
Andrade RJ:: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain

Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, 29010 Malaga, Spain
Mabe J:: IK4-Tekniker, 20600 Eibar, Spain
Simón J:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
Martínez-Chantar ML:: Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain

Keywords

acetaminophen (APAP); ammonia; drug-induced liver injury (DILI); methionine cycle; miR-873-5p; mitochondria; polyamines; therapy

Proyectos asociados

DESARROLLO DE UN MODELO HEPATOCELULAR HUMANO DIFERENCIADO PARA ESTUDIOS DE METABOLISMO Y POTENCIAL INDUCTOR DE NUEVOS FARMACOS

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SAF2003-09353 . 2003

A-CUTE-TOX

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

LSHB-CT-2004-512051-ACUTE TOX . FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2005

DESARROLLO DE NUEVAS ESTRATEGIAS DIAGNOSTICAS BASADAS EN EL ESTUDIO DE LA CAPACIDAD METABOLIZANTE DE LA PIEL Y DEL PAPEL DE LAS CELULAS DENDITRICAS EN LA INDUCCION DE LAS REACCIONES ALERGICAS FRENTE A FARMACOS

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

PARTIC PI05/2290 - FUND IMABIS . INSTITUTO DE SALUD CARLOS III; FUNDACION FIMABIS . 2007

DEVELOPMENT OF A HIGH THROUGHPUT GENOMICS-BASED TEST FOR ASSESSING GENOTOXIC AND CARCINOGENIC PROPERTIES OF CHEMICAL COMPOUNDS IN VITRO

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

CARCINOGENOMICS . COMISION EUROPEA . 2006

LINTOP

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

LSHB-CT-2006-037499 - LINTOP . FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2005

MECANISMOS TRNACRIPCIONALES IMPLICADOS EN LA ETIOLOGIA DEL HIGADO GRASO NO ALCOHOLICO. ESTUDIOS EN UN MODELO CELULAR HUMANO DE ESTEATOSIS Y APLICACION AL TRANSPLANTE DE HEPATOCITOS EN TERAPIA CELULAR.

Investigador Principal: RAMIRO JOVER ATIENZA

PI07/0550 . INSTITUTO DE SALUD CARLOS III . 2007

TU HOSPITAL INVESTIGA PARA TI

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

CCT005-07-00936 . 2007

PROYECTO CAIBER

CAI08/01/0061 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2009

FORINVITOX

Investigador Principal: MARÍA JOSÉ GÓMEZ-LECHÓN MOLINER

FORINVITOX 1, START UP 2 . REMA; UNIVERSIDAD AUTONOMA BARCELONA; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2008

RED DE INNOVACION EN TECNOLOGIAS MEDICAS Y SANITARIAS - RED ITEMAS

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

RD09/0077/00156 . INSTITUTO DE SALUD CARLOS III . 2010

CREACION Y MEJORA DE INFRAESTRUCTURAS EN MEDICINA REGENERATIVA

Investigador Principal: FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA

PLE2009-0141 ACI-PLAN E . MINISTERIO DE CIENCIA E INNOVACION; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2009

MECANISMOS TRANSCRIPCIONALES IMPLICADOS EN EL HIGADO GRASO NO ALCOHOLICO DE ORIGEN METABOLICO E IATROGENICO: INFLUENCIA DE LA RESISTENCIA A LA INSULINA

Investigador Principal: RAMIRO JOVER ATIENZA

PI10/00194 . INSTITUTO DE SALUD CARLOS III . 2010

METABONOMICA Y CITOMICA COMO NUEVOS PARADIGMAS Y ESTRATEGIAS EXPERIMENTALES PARA EL ESTUDIO DE LOS MECANISMOS DE HEPATOTOXICIDAD DE FARMACOS, PREDICCION DE SU POTENCIAL HEPATOTOXICO Y LA TRANSICION DE HEPATITIS I ATROGENICA A AUTOINMUNE.

Investigador Principal: MARÍA TERESA DONATO MARTÍN

PI10/00923 . INSTITUTO DE SALUD CARLOS III . 2010

INNOVALIV: INNOVATIVE STRATEGIES TO GENERATE HUMAN HEPATOCYTES FOR TREATMENT OF METABOLIC LIVER DISEASES: TOOLS FOR PERSONALIZED CELL THERAPY

Investigador Principal: JOSÉ VICENTE CASTELL RIPOLL

278152_INNOVALIV_PE_CASTELL_FP7-HEALTH-2011-two-st . COMISION EUROPEA . 2011

PROGRAMA DE TECNICO DE APOYO. MODALIDAD EMPRESAS

Investigador Principal: FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA

PTA2012-8060-E . MINISTERIO DE ECONOMIA Y COMPETITIVIDAD . 2013

SOLICITUD DE CENTRO I+D RAMON Y CAJAL

Investigador Principal: MARÍA ÁNGELES TORMO MAS

RYC-2012-12246 . MINISTERIO DE ECONOMIA Y COMPETITIVIDAD; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2014