title: Glycogen synthase kinase 3 inhibitor attenuates endotoxin-induced liver injury.
abstract: OBJECTIVE
  Endotoxin (lipopolysaccharide, LPS)-induced acute liver injury was attenuated by endotoxin tolerance (ET), which is characterized by phosphatidylinositol 3-kinase pathway/Akt signaling. Glycogen synthase kinase 3 (GSK-3) acts downstream of phosphatidylinositol 3-kinase pathway/Akt and GSK-3 inhibitor protects against organic injury. This study evaluates the hypothesis that ET attenuated LPS-induced liver injury through inhibiting GSK-3 functional activity and downstream signaling.
  
  
  METHODS
  Sprague-Dawley rats with or without low-dose LPS pretreatment were challenged with or without large dose of LPS and subsequently received studies. Serum tumor necrosis factor-alpha, interleukin-10, alanine aminotransferase, lactate dehydrogenase, and total bilirubin levels were analyzed, morphology of liver tissue was performed, glycogen content, myeloperoxidase content, phagocytosis activity of Kupffer cells, and the expression and inhibitory phosphorylation as well as kinase activity of GSK-3 were examined. Survival after LPS administration was also determined.
  
  
  RESULTS
  LPS induced significant increases of serum TNF-α, alanine aminotransferase, lactate dehydrogenase, and total bilirubin (P < 0.05), which were companied by obvious alterations in liver: the injury of liver tissue, the decrease of glycogen, the infiltration of neutrophils, and the enhancement of phagocytosis of Kupffer cells (P < 0.05). LPS pretreatment significantly attenuated these alterations, promoted the inhibitory phosphorylation of GSK-3 and inhibited its kinase activity, and improved the survival rate (P < 0.05).
  
  
  CONCLUSIONS
  ET attenuated LPS-induced acute liver injury through inhibiting GSK-3 functional activity and its downstream signaling.
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Jun-hua
authors.initials: JH
authors.lastname: Gong
authors.forename: Jian-ping
authors.initials: JP
authors.lastname: Gong
authors.forename: Jin-zheng
authors.initials: JZ
authors.lastname: Li
authors.forename: Kun
authors.initials: K
authors.lastname: He
authors.forename: Pei-zhi
authors.initials: PZ
authors.lastname: Li
authors.forename: Xiao-wei
authors.initials: XW
authors.lastname: Jiang
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001663:Bilirubin / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004731:Endotoxins; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007770:L-Lactate Dehydrogenase; D000410:Alanine Transaminase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D001663:Bilirubin
keywords: Attenuate; Glycogen metabolism; Glycogen synthase kinase 3; Inflammation; Inhibitor; Kupffer; Lipopolysaccharide tolerance; Liver injury; Organic protection; Phagocytosis