title: Cystathionine γ-lyase deficiency protects mice from galactosamine/lipopolysaccharide-induced acute liver failure.
abstract: OBJECTIVE
  Acute liver failure (ALF) is a fatal syndrome attributed to massive hepatocyte death. Hydrogen sulfide (H2S) has been reported to exert cytoprotective or cytotoxic effects. Here, we examined the role of cystathionine γ-lyase (CSE, an enzyme produces H2S) in ALF induced by D-Galactosamine (GalN) and lipopolysaccharide (LPS).
  
  
  RESULTS
  Wild-type (WT) mice exhibited high mortality rate, prominent liver injury, and increased plasma alanine aminotransferase levels after GalN/LPS challenge. Congenital deficiency or chemical inhibition of CSE by DL-propargylglycine attenuated GalN/LPS-induced liver injury. CSE deficiency markedly improved survival rate and attenuated GalN/LPS-induced upregulation of inflammatory cytokines and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) in the liver. CSE deficiency protected primary hepatocytes from GalN/tumor necrosis factor-α (TNF-α)-induced cell death without affecting LPS-induced TNF-α production from primary peritoneal macrophages. Beneficial effects of CSE deficiency were associated with markedly elevated homocysteine and thiosulfate levels, upregulation of NF-E2 p45-related factor 2 (Nrf2) and antioxidant proteins, activation of Akt-dependent anti-apoptotic signaling, and inhibition of GalN/LPS-induced JNK phosphorylation in the liver. Finally, administration of sodium thiosulfate (STS) attenuated GalN/LPS-induced liver injury via activation of Akt- and Nrf2-dependent signaling and inhibition of GalN/LPS-induced JNK phosphorylation in WT mice.
  
  
  METHODS
  These results suggest that inhibition of CSE or administration of STS prevents acute inflammatory liver failure by augmenting thiosulfate levels and upregulating antioxidant and anti-apoptotic defense in the liver.
  
  
  CONCLUSIONS
  Congenital deficiency or chemical inhibition of CSE increases thiosulfate levels in the liver and prevents ALF at least in part by augmentation of antioxidant and anti-apoptotic mechanisms.
authors.affiliation: 1 Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital , Charlestown, Massachusetts.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shirozu
authors.forename: Kentaro
authors.initials: K
authors.lastname: Tokuda
authors.forename: Eizo
authors.initials: E
authors.lastname: Marutani
authors.forename: David
authors.initials: D
authors.lastname: Lefer
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D003542:Cystathionine gamma-Lyase / Q000172:deficiency*; D004195:Disease Models, Animal; D005688:Galactosamine / Q000009:adverse effects*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011808:Quinone Reductases / Q000378:metabolism; D013440:Sulfides / Q000378:metabolism; D013885:Thiosulfates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D019253:Proto-Oncogene Proteins c-bcl-2; D013440:Sulfides; D013885:Thiosulfates; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D011808:Quinone Reductases; C073412:sulfide quinone reductase; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D003542:Cystathionine gamma-Lyase; C017717:sodium thiosulfate