%0 Journal Article
%A Rodríguez-Agudo, Rubén
%A Goikoetxea-Usandizaga, Naroa
%A Serrano-Maciá, Marina
%A Fernández-Tussy, Pablo
%A Fernández-Ramos, David
%A Lachiondo-Ortega, Sofía
%A González-Recio, Irene
%A Gil-Pitarch, Clàudia
%A Mercado-Gómez, María
%A Morán, Laura
%A Bizkarguenaga, Maider
%A Lopitz-Otsoa, Fernando
%A Petrov, Petar
%A Bravo, Miren
%A Van Liempd, Sebastiaan Martijn
%A Falcon-Perez, Juan Manuel
%A Zabala-Letona, Amaia
%A Carracedo, Arkaitz
%A Castell, Jose Vicente
%A Jover, Ramiro
%A Martínez-Cruz, Luis Alfonso
%A Delgado, Teresa Cardoso
%A Cubero, Francisco Javier
%A Lucena, María Isabel
%A Andrade, Raúl Jesús
%A Mabe, Jon
%A Simón, Jorge
%A Martínez-Chantar, María Luz
%T Methionine Cycle Rewiring by Targeting miR-873-5p Modulates Ammonia Metabolism to Protect the Liver from Acetaminophen.
%D 2022
%@ 2076-3921
%U http://hdl.handle.net/10668/20781
%X 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.
%K acetaminophen (APAP)
%K ammonia
%K drug-induced liver injury (DILI)
%K methionine cycle
%K miR-873-5p
%K mitochondria
%K polyamines
%K therapy
%~