title: Abnormal deposition of collagen around hepatocytes in Wilson's disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2.
abstract: OBJECTIVE
  Lysyl-oxidases catalyze the oxidation of lysine residues in collagen and elastin thereby promoting their polymerization. We have studied here the expression of four lysyl-oxidases in normal and diseased human liver.
  
  
  METHODS
  The expression of the different lysyl-oxidases in paraffin embedded liver sections was studied using in-situ hybridization and immunohistochemistry. The enzymatic activity of lysyl-oxidase like protein-2 (Loxl2 or LOR-1) using a previously described lysyl-oxidase assay.
  
  
  RESULTS
  We have found that the four lysyl-oxidases which we examined are not significantly expressed in the normal liver. By contrast, Wilson's disease and primary biliary cirrhosis (PBC) patients express lysyl-oxidase (Lox) and lysyl-oxidase like protein-2 (Loxl2 or LOR-1) in hepatocytes, and the expression is accompanied by collagen deposition around the hepatocytes. Lysyl-oxidases are also expressed in additional fibrotic liver diseases such as hepatitis B and C but in these diseases the expression is confined to the fibrotic lesions and collagen does not accumulate around hepatocytes. We have found that Loxl2 is able to oxidize lysine residues of collagen, and behaves in that respect similarly to Lox. The copper chelator D-penicillamine inhibits Loxl2 induced oxidation of collagen but the Lox inhibitor beta-aminopropionitrile did not inhibit the oxidation using a BAPN concentration at which Lox activity was completely inhibited. Loxl2 also catalyzed the oxidation of cell surface proteins on HepG2 hepatoblastoma cells and inhibited their proliferation.
  
  
  CONCLUSIONS
  Upregulation of Lox and Loxl2 in hepatocytes of Wilson's disease and PBC patients may contribute to liver damage by various mechanisms. The upregulation of Lox and Loxl2 in Wilson's disease could perhaps be utilized for diagnostic purposes since their expression is up-regulated in hepatocytes even before the onset of fibrosis.
authors: The Bruce Rappaport Faculty of Medicine, Cancer and Vascular Biology Research Center, Rappaport Family Institute for Research in the Medical Sciences, Technion, Israel Institute of Technology, P.O. Box 9697, 1 Efron St., 31096 Haifa, Israel.
authors: Zehava
authors: Z
authors: Vadasz
authors: Ofra
authors: O
authors: Kessler
authors: Gal
authors: G
authors: Akiri
authors: Stela
authors: S
authors: Gengrinovitch
authors: Herbert M
authors: HM
authors: Kagan
authors: Yaacov
authors: Y
authors: Baruch
authors: Ofer Ben
authors: OB
authors: Izhak
authors: Gera
authors: G
authors: Neufeld
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000235:genetics*; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D004730:Endothelium, Vascular / Q000201:enzymology; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D006527:Hepatolenticular Degeneration / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D017403:In Situ Hybridization; D008103:Liver Cirrhosis / Q000201:enzymology; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics*; D014162:Transfection
chemical_list: D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; D008249:Protein-Lysine 6-Oxidase