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
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
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DOI：
10.1016/j.jhep.2005.02.052
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发表时间：
2005-09-01
影响因子：
25.7
通讯作者：
Neufeld, G
中科院分区：
文献类型：
--
作者：
Vadasz, Z;Kessler, O;Neufeld, G
背景/目的：赖氨酸氧化酶催化胶原蛋白和弹性蛋白中赖氨酸残基的氧化，从而促进它们的聚合。我们研究了四种赖氨酸氧化酶在正常和患病人肝脏中的表达。方法：采用原位杂交和免疫组织化学方法研究不同赖氨酸氧化酶在石蜡包埋肝组织中的表达。赖氨酸氧化酶样蛋白-2 （Loxl2或LOR-1）的酶活性使用先前描述的赖氨酸氧化酶测定。结果：四种赖氨酸氧化酶在正常肝脏中均无明显表达。相比之下，Wilson's病和原发性胆汁性肝硬化（PBC）患者在肝细胞中表达赖氨酸氧化酶（Lox）和赖氨酸氧化酶样蛋白-2 (Loxl2或LOR-1)，并伴有肝细胞周围胶原沉积。赖氨酸氧化酶在其他纤维化性肝病如乙型肝炎和丙型肝炎中也有表达，但在这些疾病中，赖氨酸氧化酶的表达仅限于纤维化病变，胶原蛋白不会在肝细胞周围积聚。我们发现Loxl2能够氧化胶原蛋白的赖氨酸残基，并且在这方面的行为与Lox相似。铜螯合剂d -青霉胺抑制Loxl2诱导的胶原氧化，而Lox抑制剂β -氨基丙腈在BAPN浓度下对Lox活性完全抑制，没有抑制氧化作用。Loxl2还能催化HepG2肝母细胞表面蛋白的氧化，抑制其增殖。结论：肝豆状核变性和PBC患者肝细胞中Lox和Lox12的上调可能通过多种机制导致肝损伤。在Wilson病中Lox和Lox12的上调可能被用于诊断目的，因为它们的表达在肝细胞中甚至在纤维化发生之前就上调了。(c) 2005年欧洲肝脏研究协会。Elsevier BN出版。版权所有。
Background/Aims: 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 hepatoblastorna cells and inhibited their proliferation.Conclusions: Upregulation of Lox and Lox12 in hepatocytes of Wilson's disease and PBC patients may contribute to liver damage by various mechanisms. The upregulation of Lox and Lox12 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. (c) 2005 European Association for the Study of the Liver. Published by Elsevier BN. All rights reserved.