SIRT1 Controls Acetaminophen Hepatotoxicity by Modulating Inflammation and Oxidative Stress

被引:127
作者
Rada, Patricia [1 ,2 ]
Pardo, Virginia [1 ,2 ]
Mobasher, Maysa A. [1 ,2 ,3 ]
Garcia Martinez, Irma [1 ]
Ruiz, Laura [1 ,2 ]
Gonzalez-Rodriguez, Agueda [4 ]
Sanchez-Ramos, Cristina [1 ]
Muntane, Jordi [5 ,6 ]
Alemany, Susana [1 ]
James, Laura P. [7 ]
Simpson, Kenneth J. [8 ]
Monsalve, Maria [1 ]
Pilar Valdecantos, Maria [1 ,2 ]
Valverde, Angela M. [1 ,2 ]
机构
[1] UAM, CSIC, Ctr Mixto, Inst Invest Biomed Alberto Sols, Madrid, Spain
[2] Inst Salud Carlos III, Ctr Invest Biomed Red Diabet & Enfermedades Metab, Madrid, Spain
[3] Al Jouf Univ, Div Biochem, Dept Pathol, Coll Med, Sakakah, Saudi Arabia
[4] Hosp Univ Santa Cristina, Inst Invest Sanitaria Princesa, Madrid, Spain
[5] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Hepat & Digest, Madrid, Spain
[6] Univ Seville, Univ Hosp Virgen del Rocio, Oncol Surg Cell Therapy & Transplant Organs, CSIC,Inst Biomed Seville IBiS, Seville, Spain
[7] Arkansas Childrens Hosp, Sect Clin Pharmacol & Toxicol, 800 Marshall St, Little Rock, AR 72202 USA
[8] Univ Edinburgh, Div Clin & Surg Sci, Edinburgh, Midlothian, Scotland
基金
欧盟地平线“2020”;
关键词
paracetamol; SIRT1; oxidative stress; antioxidant defense; inflammation; hepatotoxicity; interleukin; 1; beta; INDUCED LIVER-INJURY; IMPROVES MITOCHONDRIAL-FUNCTION; STERILE INFLAMMATION; HEPATIC STEATOSIS; KUPFFER CELLS; MOUSE-LIVER; MICE; MACROPHAGES; INHIBITION; PROTECTS;
D O I
10.1089/ars.2017.7373
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (NF kappa B) 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)1 beta, an activator of NF kappa B. This negative modulation was abolished by neutralizing IL1 beta in APAP-CM or silencing p65-NF kappa B in hepatocytes. APAP-CM of macrophages from SIRT1-Tg mice failed to downregulate SIRT1 protein levels in hepatocytes. In vivo administration of the NF kappa B 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 IL1 beta/NF kappa B signaling in APAP hepatotoxicity, resulting in inflammation and oxidative stress. Thus, maintenance of SIRT1 during APAP overdose by inhibiting NF kappa B 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. 00, 000-000.
引用
收藏
页码:1187 / 1208
页数:22
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