Journal
JOURNAL OF HEPATOLOGY
Volume 35, Issue 3, Pages 367-375Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/S0168-8278(01)00135-0
Keywords
transglutaminase; cross-linking; liver fibrosis; extracellular matrix; alveolar echinococcosis; osteonectin; N-epsilon(gamma-glutamyl)lysine; remodeling
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Background/Aims: Lysyl oxidase-mediated cross-linking contributes to the stabilization of collagen in liver fibrosis. We have investigated transglutaminase-mediated cross-linking, to determine if it participates in the stabilization of extracellular matrix in human liver fibrosis. Methods: Transglutaminase activity was assessed in vitro by incorporation of biotinylated amine into liver proteins. The product of the transglutaminase-catalyzed cross-linking reaction, N-epsilon(gamma -glutamyl)lysine, and the extracellular proteins cross-linked by it, were localized by immunohistochemistry in fibrotic livers. The cross-linked complexes were extracted from liver tissue, immunopurified and characterized by Western blot. Results: Transglutaminase, detected by immunohistochemistry, Western blot and by enzymatic activity, was found in higher amounts in fibrotic than in normal liver. The N-epsilon(gamma -glutamyl)lysine cross-link, undetectable in normal liver, was present extracellularly in fibrotic liver, where it was co-distributed with osteonectin, mostly in inflammatory areas submitted to an intense remodeling. Cross-linking of osteonectin by transglutaminase was confirmed by Western blot. In parasitic fibrosis transglutaminase also originates from the parasite. Conclusions: Transglutaminase-mediated cross-linking occurs in liver extracellular matrix during the early, inflammatory, stage of liver fibrosis, whereas cross-linking by pyridinoline occurs mostly later in the fibrotic process. This could lead to the development of new anti-fibrotic treatments targeted to a specific stage of fibrosis. (C) 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.
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