Sestrin2 protects against acetaminophen-induced liver injury. (1st May 2017)

• Record Type: Journal Article
• Authors: Kim, Seung Jung; Kim, Kyu Min; Yang, Ji Hye; Cho, Sam Seok; Kim, Ji Young; Park, Su Jung; Lee, Sang Kyu; Ku, Sae Kwang; Cho, Il Je; Ki, Sung Hwan
• Is Part Of: Chemico-biological interactions. Volume 269(2017)
• Page Start: 50
• Page End: 58
• Publication Date: 2017-05-01
• Subjects: Sestrin2 -- Acetaminophen -- Oxidative stress -- JNK; Ad-LacZ adenovirus which expressed LacZ -- Ad-Sesn2 adenovirus which expressed Sesn2 -- ALD alcoholic liver diseases -- ALT alanine aminotransferase -- APAP acetaminophen -- AST aspartate aminotransferase -- CYPs cytochrome p450 enzymes -- CYP2E1 cytochrome P450 2E1 -- DCFH-DA 2′, 7′-dichlorofluorescin diacetate -- ELISA enzyme-linked immunosorbent assay -- GSH glutathione -- GSTs glutathione S-transferases -- H&E hematoxylin and eosin -- IL-1β interleukin-1β -- IL-6 interleukin-6 -- i.p intraperitoneally -- JNK c-jun-N-terminal kinase -- MAPKs mitogen-activated protein kinases -- NAC N-acetylcysteine -- NAPQI N-acetyl-p-benzoquinone imine -- NT nitrotyrosine -- PCNA proliferating cell nuclear antigen -- ROS reactive oxygen species -- Sesn2 Sestrin2 -- TNF-α tumor necrosis factor-α -- TUNEL terminal transferase-mediated dUTP nic end labeling -- 4-HNE 4-hydroxynonenal; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2017.02.002
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Acetaminophen (APAP) overdose accounts for half of the cases of acute liver failure worldwide. We previously reported that Sestrin2 (Sesn2) protects againstd -galactosamine/lipopolysaccharide-induced acute fulminant liver failure. In this study, we demonstrated that Sesn2 protects APAP-induced liver injury in mice, using a recombinant adenovirus encoding Sesn2 (Ad-Sesn2). First, we found that treatment of mice with toxic levels of APAP significantly reduced Sesn2 expression. Tail-vein injection with Ad-Sesn2 inhibited APAP-induced serum alanine aminotransferase and aspartate aminotransferase levels and markedly reduced hepatocyte degeneration and inflammatory cell infiltration. Additionally, APAP-induced glutathione depletion and reactive oxygen species generation were inhibited by Ad-Sesn2 treatment. Consistently, hepatic inflammatory gene expression and proinflammatory cytokine levels were also inhibited in Sesn2-infected mice, and we observed reduced APAP-mediated apoptotic signaling by terminal transferase-mediated dUTP nick-end labeling staining of the hepatic tissue. At a high dose of APAP, the mortality rate of Ad-Sesn2-infected mice was significantly lower than that of control mice. Furthermore, Sesn2 prevented APAP-induced damage through suppression of downstream mitogen-activated protein kinase pathway activation. Therefore, Sesn2 exerted a protective effect against APAP-induced acute liver damage by inhibiting oxidative stress and proinflammatory signaling. Graphical abstract: Highlights: We investigated the effect of Sesn2 on APAP toxicity. APAP significantly reduced Sesn2 expression. Ad-Sesn2 inhibited APAP-induced liver damage. Sesn2 effect is mediated by suppression of oxidative stress and inflammatory responses. Sesn2 may be a promising therapeutics target for the APAP-mediated liver injury.