[Aims]: Acetaminophen (APAP) poisoning causes acute liver failure. 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 pro-inflammatory context and oxidative stress during APAP-mediated hepatotoxicity. [Results]: SIRT1 protein levels decreased in livers from humans and mice following APAP overdose. SIRT1-Tg mice maintained higher levels of SIRT1 upon APAP injection than wild-type mice and were protected against hepatotoxicity by modulation of the antioxidant systems and restrained infl ammatory responses in the liver, with decreased oxidative stress, pro-inflammatory cytokine mRNA levels, nuclear factor kappa B (NFκB) signaling, and cell death. Mouse hepatocytes stimulated with conditioned medium of APAP-treated RAW 264.7 macrophages (APAP-CM) showed decreased SIRT1 levels; an effect mimicked by interleukin 1β (IL1β), an activator of NFκB. This negative modulation of SIRT1 by APAP-CM was abolished by neutralizing IL1β in APAP-CM or silencing p65-NFκB in hepatocytes. Moreover, 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 protein levels and protected from APAP-mediated acute hepatotoxicity. [Innovation]: Our work has evidenced the unique role of SIRT1 in protection against APAP-mediated hepatotoxicity by targeting oxidative stress and inflammation. [Conclusion]: SIRT1 protein levels are negatively downregulated by IL1β/NFκB signaling in response to APAP overdose, and this downregulation is involved in oxidative stress during APAP hepatotoxicity. Thus, maintenance of SIRT1 during APAP overdose by inhibiting NFκB might be clinically relevant.

Resumen del póster presentado al 1st Joint Meeting of the French-Portuguese-Spanish Biochemical and Molecular Biology Societies y al XL Spanish Society of Biochemistry and Molecular Biology (SEBBM) Congress, celebrado en Barcelona (España) del 23 al 26 de octubre de 2017.

Peer Reviewed