HBx facilitates ferroptosis in acute liver failure via EZH2 mediated SLC7A11 suppression

被引:103
作者
Liu, Guo-Zhen [1 ]
Xu, Xu-Wen [2 ]
Tao, Shu-Hui [3 ]
Gao, Ming-Jian [1 ]
Hou, Zhou-Hua [1 ]
机构
[1] Cent South Univ, Dept Infect Dis, Xiangya Hosp, 87 Xiangya Rd, Changsha 410008, Hunan, Peoples R China
[2] Southern Med Univ, Nanfang Hosp, Dept Infect Dis, Guangzhou 510515, Guangdong, Peoples R China
[3] Southern Med Univ, Shenzhen Hosp, Dept Liver Dis, Shenzhen 518100, Guangdong, Peoples R China
关键词
Acute liver failure; Ferroptosis; HBx; EZH2; OXIDATIVE STRESS; HEPATOCELLULAR-CARCINOMA; CELL-DEATH; HEPATITIS; INJURY; ANTIOXIDANTS;
D O I
10.1186/s12929-021-00762-2
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Background Acute liver failure (ALF) is a syndrome of severe hepatocyte injury with high rate of mortality. Hepatitis B virus (HBV) infection is the major cause of ALF worldwide, however, the underlying mechanism by which HBV infection leads to ALF has not been fully disclosed. Methods D-GalN-induced hepatocyte injury model and LPS/D-GalN-induced ALF mice model were used to investigate the effects of HBV X protein (HBx) in vitro and in vivo, respectively. Cell viability and the levels of Glutathione (GSH), malondialdehyde (MDA) and iron were measured using commercial kits. The expression of ferroptosis-related molecules were detected by qRT-PCR and western blotting. Epigenetic modification and protein interaction were detected by chromatin immunoprecipitation (ChIP) assay and co-immunoprecipitation (co-IP), respectively. Mouse liver function was assessed by measuring aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The histological changes in liver tissues were monitored by hematoxylin and eosin (H&E) staining, and SLC7A11 immunoreactivity was assessed by immunohistochemistry (IHC) analysis. Results D-GalN triggered ferroptosis in primary hepatocytes. HBx potentiated D-GalN-induced hepatotoxicity and ferroptosis in vitro, and it suppressed SLC7A11 expression through H3K27me3 modification by EZH2. In addition, EZH2 inhibition or SLC7A11 overexpression attenuated the effects of HBx on D-GalN-induced ferroptosis in primary hepatocytes. The ferroptosis inhibitor ferrostatin-1 (Fer-1) protected against ALF and ferroptosis in vivo. By contrast, HBx exacerbates LPS/D-GalN-induced ALF and ferroptosis in HBx transgenic (HBx-Tg) mice. Conclusion HBx facilitates ferroptosis in ALF via EZH2/H3K27me3-mediated SLC7A11 suppression.
引用
收藏
页数:13
相关论文
共 39 条
[1]   Hepatitis B virus X protein enhances the development of liver fibrosis and the expression of genes associated with epithelial-mesenchymal transitions and tumor progenitor cells [J].
Ahodantin, James ;
Lekbaby, Bouchra ;
Nader, Myriam Bou ;
Soussan, Patrick ;
Kremsdorf, Dina .
CARCINOGENESIS, 2020, 41 (03) :358-367
[2]   Clinical Outcome and Viral Genome Variability of Hepatitis B Virus-Induced Acute Liver Failure [J].
Anastasiou, Olympia E. ;
Widera, Marek ;
Westhaus, Sandra ;
Timmer, Lejla ;
Korth, Johannes ;
Gerken, Guido ;
Canbay, Ali ;
Todt, Daniel ;
Steinmann, Eike ;
Schwarz, Tatjana ;
Timm, Joerg ;
Verheyen, Jens ;
Ciesek, Sandra .
HEPATOLOGY, 2019, 69 (03) :993-1003
[3]  
Aparicio-Vergara M, 2017, METHODS MOL BIOL, V1639, P161, DOI 10.1007/978-1-4939-7163-3_16
[4]   Role of histone H3 lysine 27 methylation in polycomb-group silencing [J].
Cao, R ;
Wang, LJ ;
Wang, HB ;
Xia, L ;
Erdjument-Bromage, H ;
Tempst, P ;
Jones, RS ;
Zhang, Y .
SCIENCE, 2002, 298 (5595) :1039-1043
[5]   Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis [J].
Dixon, Scott J. ;
Patel, Darpan ;
Welsch, Matthew ;
Skouta, Rachid ;
Lee, Eric ;
Hayano, Miki ;
Thomas, Ajit G. ;
Gleason, Caroline ;
Tatonetti, Nicholas ;
Slusher, Barbara S. ;
Stockwell, Brent R. .
ELIFE, 2014, 3
[6]   Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death [J].
Dixon, Scott J. ;
Lemberg, Kathryn M. ;
Lamprecht, Michael R. ;
Skouta, Rachid ;
Zaitsev, Eleina M. ;
Gleason, Caroline E. ;
Patel, Darpan N. ;
Bauer, Andras J. ;
Cantley, Alexandra M. ;
Yang, Wan Seok ;
Morrison, Barclay, III ;
Stockwell, Brent R. .
CELL, 2012, 149 (05) :1060-1072
[7]   Prodromal fever indicates a high risk of liver failure in acute hepatitis B [J].
Du, Wen-Jun ;
Liu, Li ;
Sun, Chao ;
Yu, Jin-Hong ;
Xiao, Di ;
Li, Qiang .
INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 2017, 57 :98-103
[8]   HBx Protein Contributes to Liver Carcinogenesis by H3K4me3 Modification Through Stabilizing WD Repeat Domain 5 Protein [J].
Gao, Weiwu ;
Jia, Zhengcai ;
Tian, Yi ;
Yang, Penghui ;
Sun, Hui ;
Wang, Chenhui ;
Ding, Yi ;
Zhang, Mengjie ;
Zhang, Yi ;
Yang, Di ;
Tian, Zhiqiang ;
Zhou, Jian ;
Ruan, Zhihua ;
Wu, Yuzhang ;
Ni, Bing .
HEPATOLOGY, 2020, 71 (05) :1678-1695
[9]   Oxidative stress and antioxidants in hepatic pathogenesis [J].
Ha, Hye-Lin ;
Shin, Hye-Jun ;
Feitelson, Mark A. ;
Yu, Dae-Yeul .
WORLD JOURNAL OF GASTROENTEROLOGY, 2010, 16 (48) :6035-6043
[10]   Hepatitis B virus transcriptional activators: Mechanisms and possible role in oncogenesis [J].
Henkler, F ;
Koshy, R .
JOURNAL OF VIRAL HEPATITIS, 1996, 3 (03) :109-121