title: Inhibition of glycogen synthase kinase 3β ameliorates D-GalN/LPS-induced liver injury by reducing endoplasmic reticulum stress-triggered apoptosis.
abstract: BACKGROUND
  Glycogen 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).
  
  
  METHODS
  In 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.
  
  
  RESULTS
  GSK3β 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: The 2nd Department of Infectious Diseases, the 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People's Republic of China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Chen
authors.forename: Feng
authors.initials: F
authors.lastname: Ren
authors.forename: Haiyan
authors.initials: H
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Wen
authors.forename: Zhengfu
authors.initials: Z
authors.lastname: Piao
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Sujun
authors.initials: S
authors.lastname: Zheng
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Yuanping
authors.initials: Y
authors.lastname: Han
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Duan
authors.forename: Yingji
authors.initials: Y
authors.lastname: Ma
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053454:Caspase 12 / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005688:Galactosamine; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D008297:Male; D008301:Maleimides / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000637:Transaminases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C497250:Ddit3 protein, mouse; D004791:Enzyme Inhibitors; D007211:Indoles; D008070:Lipopolysaccharides; D008301:Maleimides; C417521:SB 216763; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051742:Transcription Factor CHOP; D005688:Galactosamine; D000637:Transaminases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D053454:Caspase 12