Abstract
ObjectiveOur previous studies have demonstrated that glycogen synthase kinase 3β (GSK3β) activity is increased in the progression of acute liver failure (ALF), which aggravates liver injury, while its regulatory mechanism remains elusive. This study is designated to address whether oxidative stress activates GSK3β to promote ALF.MethodsIn a murine model induced by d-galactosamine (d-GalN) (700 mg/kg) and LPS (10 μg/kg), N-acetylcysteine (300 mg/kg) or SB216763 (25 mg/kg) was used to inhibit oxidative stress or GSK3β activity, respectively. Serum alanine aminotransferase and aspartate aminotransferase levels were assessed. The parameters of oxidative stress were evaluated in liver tissue. Whether GSK3β inhibition protects hepatocytes from oxidative stress-induced cell apoptosis was investigated in vitro. Moreover, the activity of GSK3β was measured in the liver of chronic hepatitis B (CHB) patients and ALF patients.ResultsIn vivo, N-acetylcysteine ameliorated the d-GalN/LPS-induced hepatotoxicity and reduced GSK3β activity; GSK3β inhibition increased hepatic superoxide dismutase activity and the glutathione content, decreased malondialdehyde production in the liver tissues; while GSK3β inhibition suppressed the JNK activation in the liver and decreased cytochrome c release from mitochondria. In vitro, GSK3β inhibition lessened hepatocytes apoptosis induced by H2O2 or Antimycin A, as demonstrated by decreased LDH activity, and reduced cleavage of caspase-3 expression. Furthermore, GSK3β activity in the CHB patients was increased in the phase of ALF.ConclusionsResults indicate that GSK3β activation contributes to liver injury by participating in oxidative stress response in ALF and is, therefore, a potential therapeutic target for ALF.
Highlights
Acute liver failure (ALF, sometimes referred to as fulminant hepatic failure) is a severe liver disease characterized by encephalopathy and coagulopathy in patients with previously normal liver function [1,2,3]
Results indicate that glycogen synthase kinase 3b (GSK3b) activation contributes to liver injury by participating in oxidative stress response in acute liver failure (ALF) and is, a potential therapeutic target for ALF
Hydrogen peroxide Lactate dehydrogenase Cytochrome c Sodium dodecyl sulfate Polyacrylamide gel electrophoresis; 40,6-diamidino-2-phenylindole this hypothesis, we performed experiments to evaluate the oxidative stress during the progression of ALF, to investigate GSK3b inhibition in regulating oxidative stress through both the in vivo and in vitro models
Summary
Acute liver failure (ALF, sometimes referred to as fulminant hepatic failure) is a severe liver disease characterized by encephalopathy and coagulopathy in patients with previously normal liver function [1,2,3]. In China, ALF is a serious consequence of the acute exacerbation of hepatitis B virus (HBV) infection. The ALF has been created by an animal model induced by the co-injection of D-galactosamine (D-GalN) and lipopolysaccharides (LPS), which has been widely used to examine the mechanisms underlying ALF [4, 5]. Identified in mammals as a cytoplasmic modulator of glycogen metabolism, GSK3b is recognized as a central regulator of cellular events, including cell fate determination, microtubule function, cell cycle regulation, apoptosis, and inflammatory responses [6,7,8,9,10,11]. Our previous study showed that GSK3b is activated in the progression of ALF induced by D-GalN/LPS, and GSK3b inhibition can ameliorate hepatotoxicity in ALF mice [12], while its regulatory mechanism is very poorly understood
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