Abstract
BackgroundAcute 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.MethodsD-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.ResultsD-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.ConclusionHBx facilitates ferroptosis in ALF via EZH2/H3K27me3-mediated SLC7A11 suppression.
Highlights
Acute liver failure (ALF) is a syndrome of severe hepatocyte injury with high rate of mortality
Ferroptosis is activated in D‐GalN‐induced hepatocyte injury model
The upregulation of H3K27me3 is more prominent in HBV X protein (HBx)-Tg + LPS/D-GalN mice, and GSK126 partially abolished LPS/D-GalN-increased H3K27me3 expression in both WT and HBx transgenic (HBx-Tg) mice. These findings suggest that HBx exacerbates LPS/D-GalNinduced ALF and ferroptosis in vivo, possibly via suppressing solute carrier family 7 membrane 11 (SLC7A11)
Summary
Acute liver failure (ALF) is a syndrome of severe hepatocyte injury with high rate of mortality. Acute liver failure (ALF) is a syndrome of severe hepatocyte injury characterized with rapid-onset elevation of aminotransferases and disturbed coagulation and mentation [1]. The mortality of ALF declines with the widespread availability of liver transplantation, the clinical outcomes remain unfavorable due to the major limitations of liver transplantation, such as organ shortage, Ferroptosis is characterized by iron-driven lipid peroxidation and accumulation of reactive oxygen species (ROS) [4]. Oxidative stress has been recognized as a key contributor to D-GalN/LPS-induced hepatotoxicity [12]. Given the role of ferroptosis in oxidative stress, we speculated that D-GalN might trigger ferroptosis to induce accumulation of ROS, leading to ALF. The regulatory mechanism of ferroptosis in ALF merits further investigation
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