title: Expression of glyoxalase-I is reduced in cirrhotic livers: A possible mechanism in the development of cirrhosis.
abstract: BACKGROUND
  High concentrations of methylglyoxal (MGO) cause cytotoxiticy via formation of advanced glycation endproducts (AGEs) and inflammation. MGO is detoxificated enzymatically by glyoxalase-I (Glo-I). The aim of this study was to analyze the role of Glo-I during the development of cirrhosis.
  
  
  METHODS
  In primary hepatocytes, hepatic stellate cells (pHSC) and sinusoidal endothelial cells (pLSEC) from rats with early (CCl4 8wk) and advanced cirrhosis (CCl4 12wk) expression and activity of Glo-I were determined and compared to control. LPS stimulation (24h; 100ng/ml) of HSC was conducted in absence or presence of the partial Glo-I inhibitor ethyl pyruvate (EP) and the specific Glo-I inhibitor BrBzGSHCp2. MGO, inflammatory and fibrotic markers were measured by ELISA and Western blot. Additional rats were treated with CCl4 ± EP 40mg/kg b.w. i.p. from wk 8-12 and analyzed with sirius red staining and Western blot.
  
  
  RESULTS
  Expression of Glo-I was significantly reduced in cirrhosis in whole liver and primary liver cells accompanied by elevated levels of MGO. Activity of Glo-I was reduced in cirrhotic pHSC and pLSEC. LPS induced increases of TNF-α, Nrf2, collagen-I, α-SMA, NF-kB and pERK of HSC were blunted by EP and BrBzGSHCp2. Treatment with EP during development of cirrhosis significantly decreased the amount of fibrosis (12wk CCl4: 33.3±7.3%; EP wk 8-12: 20.7±6.2%; p<0.001) as well as levels of α-SMA, TGF-β and NF-κB in vivo.
  
  
  CONCLUSIONS
  Our results show the importance of Glo-I as major detoxifying enzyme for MGO in cirrhosis. The reduced expression of Glo-I in cirrhosis demonstrates a possible explanation for increased inflammatory injury and suggests a "vicious circle" in liver disease. Blunting of the Glo-I activity decrease the amount of fibrosis in established cirrhosis and constitutes a novel target for antifibrotic therapy.
authors.affiliation: Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Hollenbach
authors.affiliation: Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Thonig
authors.affiliation: Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Pohl
authors.affiliation: Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ripoll
authors.affiliation: Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: Maurice
authors.initials: M
authors.lastname: Michel
authors.affiliation: Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zipprich
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D007791:Lactoylglutathione Lyase / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D008103:Liver Cirrhosis / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D008297:Male; D016328:NF-kappa B / Q000276:immunology; D011765:Pyruvaldehyde / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C099177:S-4-bromobenzylglutathione cyclopentyl diester; D011765:Pyruvaldehyde; D007791:Lactoylglutathione Lyase; D005978:Glutathione