Oxidative stress promotes D-GalN/LPS-induced acute hepatotoxicity by increasing glycogen synthase kinase 3b activity

The Author(s) 2014. This article is published with open access at Springerlink.com Objective Our previous studies have demonstrated that glycogen synthase kinase 3b (GSK3b) 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 whe-ther oxidative stress activates GSK3b to promote ALF. Methods In a murine model induced by D-galactosamine (D-GalN) (700 mg/kg) and LPS (10 lg/kg), N-acetylcys-teine (300 mg/kg) or SB216763 (25 mg/kg) was used to inhibit oxidative stress or GSK3b activity, respectively. Serum alanine aminotransferase and aspartate aminotrans-ferase levels were assessed. The parameters of oxidative stress were evaluated in liver tissue. Whether GSK3b inhibition protects hepatocytes from oxidative stress-induced cell apoptosis was investigated in vitro. Moreover, the activity of GSK3b was measured in the liver of chronic hepatitis B (CHB) patients and ALF patients. Results In vivo, N-acetylcysteine ameliorated the D-GalN/LPS-induced hepatotoxicity and reduced GSK3b activity; GSK3b inhibition increased hepatic superoxide dismutase activity and the glutathione content, decreased malondialdehyde production in the liver tissues; while GSK3b inhibition suppressed the JNK activation in the liver and decreased cytochrome c release from mitochon-dria. In vitro, GSK3b inhibition lessened hepatocytes apoptosis induced by H2O2 or Antimycin A, as demon-strated by decreased LDH activity, and reduced cleavage of caspase-3 expression. Furthermore, GSK3b activity in the CHB patients was increased in the phase of ALF. Conclusions Results indicate that GSK3b activation contributes to liver injury by participating in oxidative stress response in ALF and is, therefore, a potential ther-apeutic target for ALF