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  • Title: [Role of endoplasmic reticulum stress-mediated glycogen synthase kinase 3β activity in pathogenesis of acute liver failure in mice].
    Author: Gao H, Zhang XY, Yue LY, Liu ZY, Jia NN, Chen DX, Duan ZP, Ren F.
    Journal: Zhonghua Yi Xue Za Zhi; 2016 Sep 13; 96(34):2734-2738. PubMed ID: 27667108.
    Abstract:
    Objective: To study the role of endoplasmic reticulum (ER) stress-mediated glycogen synthase kinase 3β (GSK3β) activity in the pathological process of liver injury in acute liver failure (ALF) mice. Methods: ALF model was established by intraperitoneal injection of D-galactosamine/lipopolysaccharide (D-GalN/LPS) in C57BL/6 mice. The mice were divided into control group (n=10), ALF model group (n=18), 4-phenylbutyrate (4-PBA, an ER stress inhibitor) group (n=18) and SB216763 (a specific inhibitor of GSK3β) group (n=16). The serum alanine transaminase (ALT) and aspartate transaminase (AST) levels were measured to reflect the liver function, liver injury was assessed by observing pathological changes of liver tissue, the levels of proteins in liver tissue were analyzed by Western blotting, the activity of GSK3β in liver tissue was detected using GSK3β activity assay kit, and the survival rate of hepatocyte was measured by methyl thiazolyl tetrazolium (MTT) assay. Results: In in vivo experiment, the expression levels of ER stress markers, glucose-regulated protein 78 (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP), were upregulated during the progression of D-GalN/LPS-induced ALF, indicating activation of severe ER stress and increased activity of GSK3β. Compared with the model group, inhibition of ER stress by 4-PBA improved liver function[ALT: (365.4±58.6) U/L vs (1 094.5±201.5) U/L, P<0.05; AST: (555.1±60.8) U/L vs (1 444.3±533.7) U/L, P<0.05)and pathological injury, also decreased the activity of GSK3β (2.6±0.3 vs 4.6±1.3, P<0.05). Inhibition of GSK3β activity was shown to alleviate liver injury in ALF by reducing the expression levels of GRP78 and CHOP. The in vitro experiment of tunicamycin-induced hepatocyte apoptosis showed that inhibition of GSK3β activity increased the cell survival rate. Conclusion: In ALF induced by D-GalN/LPS, severe ER stress may accelerate the development and progress of ALF by upregulating the activity of GSK3β.
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