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Title: SIRT1 Controls Acetaminophen Hepatotoxicity by Modulating Inflammation and Oxidative Stress.
Authors: Rada, Patricia
Pardo, Virginia
Mobasher, Maysa A
García-Martínez, Irma
Ruiz, Laura
González-Rodríguez, Águeda
Sanchez-Ramos, Cristina
Muntané, Jordi
Alemany, Susana
James, Laura P
Simpson, Kenneth J
Monsalve, María
Valdecantos, Maria Pilar
Valverde, Ángela M
Keywords: SIRT1;antioxidant defense;hepatotoxicity;inflammation;interleukin 1β;oxidative stress;paracetamol
metadata.dc.subject.mesh: Acetaminophen
Cell Death
Cells, Cultured
Mice, Inbred C57BL
Oxidative Stress
RAW 264.7 Cells
Sirtuin 1
Issue Date: 11-Dec-2017
Abstract: 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. 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. Our work evidenced the unique role of SIRT1 in APAP hepatoprotection by targeting oxidative stress and inflammation. 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.
metadata.dc.identifier.doi: 10.1089/ars.2017.7373
Appears in Collections:Producción 2020

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