RT Journal Article
T1 SIRT1 Controls Acetaminophen Hepatotoxicity by Modulating Inflammation and Oxidative Stress.
A1 Rada, Patricia
A1 Pardo, Virginia
A1 Mobasher, Maysa A
A1 García-Martínez, Irma
A1 Ruiz, Laura
A1 González-Rodríguez, Águeda
A1 Sanchez-Ramos, Cristina
A1 Muntané, Jordi
A1 Alemany, Susana
A1 James, Laura P
A1 Simpson, Kenneth J
A1 Monsalve, María
A1 Valdecantos, Maria Pilar
A1 Valverde, Ángela M
K1 SIRT1
K1 antioxidant defense
K1 hepatotoxicity
K1 inflammation
K1 interleukin 1β
K1 oxidative stress
K1 paracetamol
AB 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.
YR 2017
FD 2017-12-11
LK http://hdl.handle.net/10668/11747
UL http://hdl.handle.net/10668/11747
LA en
DS RISalud
RD Apr 20, 2025