- 作者: Guo-Zhen Liu, Xu-Wen Xu, Shu-Hui Tao, Ming-Jian Gao & Zhou-Hua Hou
- 作者服務機構: 1.Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China 2.Department of Infectious Diseases, Xiangya Hospital, Central South University, No.87, Xiangya Road, Kaifu District, Changsha, 410008, Hunan, China 3.Department of Liver Diseases, Shenzhen Hospital, Southern Medical University, Shenzhen, 518100, Guangdong, China
- 中文摘要:
- 英文摘要:
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. - 中文關鍵字:
- 英文關鍵字: Acute liver failure, Ferroptosis, HBx, EZH2, SLC7A11