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

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. The expression of the different lysyl-oxidases in paraffin embedded liver sections w...

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Bibliographic Details
Published in:Journal of hepatology 2005-09, Vol.43 (3), p.499-507
Main Authors: Vadasz, Zehava, Kessler, Ofra, Akiri, Gal, Gengrinovitch, Stela, Kagan, Herbert M., Baruch, Yaacov, Izhak, Ofer Ben, Neufeld, Gera
Format: Article
Language:English
Subjects:
Amino Acid Oxidoreductases - genetics
Animals
Biological and medical sciences
Cell Line, Tumor
Cercopithecus aethiops
Cloning, Molecular
Collagen
COS Cells
Endothelium, Vascular - enzymology
Extracellular-matrix
Gastroenterology. Liver. Pancreas. Abdomen
Hepatocytes - enzymology
Hepatocytes - pathology
Hepatolenticular Degeneration - enzymology
Hepatolenticular Degeneration - pathology
Humans
In Situ Hybridization
Liver Cirrhosis - enzymology
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Lysyl oxidases
Medical sciences
Metabolic diseases
Metals (hemochromatosis...)
Other diseases. Semiology
Other metabolic disorders
Primary biliary cirrhosis
Protein-Lysine 6-Oxidase - genetics
Transfection
Wilson's disease
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Summary: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. 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. 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 β-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. 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.
ISSN:0168-8278
1600-0641
DOI:10.1016/j.jhep.2005.02.052