Abstract
BackgroundGlycogen synthase kinase 3β(GSK3β) is a ubiquitous serine-threonine protein kinase that participates in numerous cellular processes and disease pathophysiology. We aimed to determine therapeutic potential of GSK3β inhibition and its mechanism in a well-characterized model of lipopolysaccharide (LPS)-induced model of acute liver failure (ALF).MethodologyIn a murine ALF model induced by D-GalN(700 mg/kg)/LPS(10 µg/kg), we analyzed GSK3β mechanisms using a specific chemical inhibitor, SB216763, and detected the role of endoplasmic reticulum stress (ERS). Mice were administered SB216763 at 2 h before or after D-GalN/LPS injection, respectively, and then sacrificed 6 h after D-GalN/LPS treatment to evaluate its prophylactic and therapeutic function. The lethality rate, liver damage, ERS, cytokine expression, MAP kinase, hepatocyte apoptosis and expression of TLR 4 were evaluated, respectively. Whether the inhibition of GSK3β activation protected hepatocyte from ERS-induced apoptosis was investigated in vitro.Principal FindingsGSK3β became quickly activated (dephosphorylated) upon D-GalN/LPS exposure. Administration of SB216763 not only ameliorated liver injury, as evidenced by reduced transaminase levels, and well-preserved liver architecture, but also decreased lethality. Moreover, GSK3β inhibition resulted in down-regulation of pro-apoptotic proteins C/EBP–homologous protein(CHOP) and caspase-12, which are related to ERS. To further demonstrate the role of ERS, we found that GSK3β inhibition protected hepatocyte from ERS-induced cell death. GSK3β inhibition down-regulated the MAPK pathways, reduced expression of inflammatory cytokines and decreased expression of TLR4.ConclusionsOur findings demonstrate the key function of GSK3β signaling in the pathophysiology of ALF, especially in regulating the ERS, and provide a rationale for targeting GSK3β as a potential therapeutic strategy to ameliorate ALF.
Highlights
Acute liver failure (ALF) is a dramatic clinical syndrome that results from massive hepatocyte death
Our findings demonstrate the key function of GSK3b signaling in the pathophysiology of acute liver failure (ALF), especially in regulating the endoplasmic reticulum stress (ERS), and provide a rationale for targeting GSK3b as a potential therapeutic strategy to ameliorate ALF
Our results demonstrated a pivotal role of GSK3b in regulating inflammatory process and hepatocyte apoptosis, in the hepatocyte apoptosis induced by ERS in acute liver failure, and revealed the clinical potential of GSK3b inhibition in preventive and therapeutic applications for acute liver failure
Summary
Acute liver failure (ALF) is a dramatic clinical syndrome that results from massive hepatocyte death. ER maintains as a cellular sensing system handling variety of stresses ranging from excessive accumulation of proteins, misfolding of proteins, and the sustained loss of Ca2+ from lumen of ER. These lead to adaptive responses that dampen the stress or to pathological responses designed to kill the cells themselves that are unable to adequately adapt the stress. Compelling evidence suggests that c-jun-N-terminal kinase (JNK), C/EBP–homologous protein (CHOP) and the caspase 12 in rodents (caspase 4 in humans) are recruited to participate in ERS-induced apoptosis [10,11]. We aimed to determine therapeutic potential of GSK3b inhibition and its mechanism in a well-characterized model of lipopolysaccharide (LPS)-induced model of acute liver failure (ALF)
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