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Título: | SIRT1 controls acetaminophen hepatotoxicity by modulating inflammation and oxidative stress |
Autor: | Rada, Patricia CSIC ORCID; Pardo, Virginia CSIC ORCID; Mobasher, Maysa A. CSIC; García Martínez, Irma; Ruiz, Laura; González-Rodríguez, Águeda CSIC ORCID; Sánchez-Ramos, Cristina CSIC ORCID; Muntané, Jordi CSIC ORCID; Alemany, Susana CSIC ORCID; James, Laura P.; Simpson, Kenneth J.; Monsalve, María CSIC ORCID ; Valdecantos, M. P. CSIC ORCID; Valverde, Ángela M. CSIC ORCID | Palabras clave: | Paracetamol Oxidative stress Antioxidant defences SIRT1 Interleukin 1β Hepatotoxicity Inflammation |
Fecha de publicación: | 2018 | Editor: | Mary Ann Liebert | Citación: | Antioxidants and Redox Signaling 28(13): 1187-1208 (2018) | Resumen: | [Aims]: Sirtuin 1 (SIRT1) is a key player in liver physiology and a therapeutic target against hepatic inflammation. We evaluated the role of SIRT1 in the proinflammatory context and oxidative stress during acetaminophen (APAP)-mediated hepatotoxicity. [Results]: SIRT1 protein levels decreased in human and mouse livers following APAP overdose. SIRT1-Tg mice maintained higher levels of SIRT1 on APAP injection than wild-type mice and were protected against hepatotoxicity by modulation of antioxidant systems and restrained inflammatory responses, with decreased oxidative stress, proinflammatory cytokine messenger RNA levels, nuclear factor kappa B (NFκB) signaling, and cell death. Mouse hepatocytes stimulated with conditioned medium of APAP-treated macrophages (APAP-CM) showed decreased SIRT1 levels; an effect mimicked by interleukin (IL)1β, an activator of NFκB. This negative modulation was abolished by neutralizing IL1β in APAP-CM or silencing p65-NFκB in hepatocytes. APAP-CM of macrophages from SIRT1-Tg mice failed to downregulate SIRT1 protein levels in hepatocytes. In vivo administration of the NFκB inhibitor BAY 11-7082 preserved SIRT1 levels and protected from APAP-mediated hepatotoxicity. [Inovation]: Our work evidenced the unique role of SIRT1 in APAP hepatoprotection by targeting oxidative stress and inflammation. [Conclusion]: SIRT1 protein levels are downregulated by IL1β/NFκB signaling in APAP hepatotoxicity, resulting in inflammation and oxidative stress. Thus, maintenance of SIRT1 during APAP overdose by inhibiting NFκB might be clinically relevant. [Rebound Track]: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16:293-296, 2012) with the following serving as open reviewers: Rafael de Cabo, Joaquim Ros, Kalervo Hiltunen, and Neil Kaplowitz. Antioxid. Redox Signal. 28, 1187-1208. |
Descripción: | ARS Open. | Versión del editor: | http://doi.org/10.1089/ars.2017.7373 | URI: | http://hdl.handle.net/10261/172954 | Identificadores: | issn: 1523-0864 e-issn: 1557-7716 |
Aparece en las colecciones: | (IBIS) Artículos (IIBM) Artículos |
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ars.SIRT1.pdf | 2,3 MB | Adobe PDF | Visualizar/Abrir |
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