Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/18632
Title
Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen.
Author(s)
Rodríguez-Agudo, Rubén | Goikoetxea-Usandizaga, Naroa | Serrano-Maciá, Marina | Fernández-Tussy, Pablo | Fernández-Ramos, David | Lachiondo-Ortega, Sofía | González-Recio, Irene | Gil-Pitarch, Clàudia | Mercado-Gómez, María | Morán, Laura | Bizkarguenaga, Maider | Lopitz-Otsoa, Fernando | Petrov, Petar | Bravo, Miren | Van Liempd, Sebastiaan Martijn | Falcon-Perez, Juan Manuel | Zabala-Letona, Amaia | Carracedo, Arkaitz | Castell, Jose Vicente | Jover, Ramiro | Martínez-Cruz, Luis Alfonso | Delgado, Teresa Cardoso | Cubero, Francisco Javier | Lucena, María Isabel | Andrade, Raúl Jesús | Mabe, Jon | Simón, Jorge | Martínez-Chantar, María Luz
Date issued
2022-04-30
Language
Inglés
Document type
research article
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.
Subject
acetaminophen (APAP) | ammonia | drug-induced liver injury (DILI) | methionine cycle | miR-873-5p | mitochondria | polyamines | therapy
DOI
Collections
- Investigación > IIS > IIS BioBizkaia - Asociación Instituto de Investigación Sanitaria BioBizkaia (País Vasco)
- Investigación > IIS > IBIMA-Plataforma BIONAND - Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina (Andalucía)
- Investigación > IIS > IIS La Fe - Fundación para la Investigación del Hospital Universitario La Fe (C. Valenciana)
- Investigación > IIS > IiSGM - Instituto de Investigación Sanitaria Gregorio Marañón (Madrid)
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