SIRT1 Controls Acetaminophen Hepatotoxicity by Modulating Inflammation and Oxidative Stress.
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.


INNOVATION
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.
['Rada|Patricia|P|', 'Pardo|Virginia|V|', 'Mobasher|Maysa A|MA|', 'García-Martínez|Irma|I|', 'Ruiz|Laura|L|', 'González-Rodríguez|Águeda|Á|', 'Sanchez-Ramos|Cristina|C|', 'Muntané|Jordi|J|', 'Alemany|Susana|S|', 'James|Laura P|LP|', 'Simpson|Kenneth J|KJ|', 'Monsalve|María|M|', 'Valdecantos|Maria Pilar|MP|', 'Valverde|Ángela M|ÁM|']
D000082:Acetaminophen D000818:Animals D016923:Cell Death D002478:Cells, Cultured D006801:Humans D007249:Inflammation D008099:Liver D008264:Macrophages D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018384:Oxidative Stress D000067996:RAW 264.7 Cells D056564:Sirtuin 1
SIRT1 hepatotoxicity inflammation oxidative stress antioxidant defense interleukin 1β paracetamol