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.
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.
Vadasz
Zehava
Z
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.
Kessler
Ofra
O
Akiri
Gal
G
Gengrinovitch
Stela
S
Kagan
Herbert M
HM
Baruch
Yaacov
Y
Izhak
Ofer Ben
OB
Neufeld
Gera
G
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
D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human; D008249:Protein-Lysine 6-Oxidase