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Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice
Author(s) -
Liu Susan B.,
Ikenaga Naoki,
Peng ZhenWei,
Sverdlov Deanna Y.,
Greenstein Andrew,
Smith Victoria,
Schuppan Detlef,
Popov Yury
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-268425
Subject(s) - lysyl oxidase , fibrosis , hepatic fibrosis , hepatic stellate cell , chemistry , pathology , in vivo , carbon tetrachloride , ccl4 , cancer research , medicine , extracellular matrix , biology , biochemistry , microbiology and biotechnology , organic chemistry
Collagen stabilization through irreversible cross‐linking is thought to promote hepatic fibrosis progression and limit its reversibility. However, the mechanism of this process remains poorly defined. We studied the functional contribution of lysyl oxidase (LOX) to collagen stabilization and hepatic fibrosis progression/reversal in vivo using chronic administration of irreversible LOX inhibitor β‐aminopropionitrile (BAPN, or vehicle as control) in C57Bl/6J mice with carbon tetrachloride (CCl 4 )‐induced fibrosis. Fibrotic matrix stability was directly assessed using a stepwise collagen extraction assay and fibrotic septae morphometry. Liver cells and fibrosis were studied by histologic, biochemical methods and quantitative real‐time reverse‐transcription PCR. During fibrosis progression, BAPN administration suppressed accumulation of cross‐linked collagens, and fibrotic septae showed widening and collagen fibrils splitting, reminiscent of remodeling signs observed during fibrosis reversal. LOX inhibition attenuated hepatic stellate cell activation markers and promoted F4/80‐positive scar‐associated macrophage infiltration without an increase in liver injury. In reversal experiments, BAPN‐treated fibrotic mice demonstrated accelerated fibrosis reversal after CCl4 withdrawal. Our findings demonstrate for the first time that LOX contributes significantly to collagen stabilization in liver fibrosis, promotes fibrogenic activation of attenuated hepatic stellate cells, and limits fibrosis reversal. Our data support the concept of pharmacologic targeting of LOX pathway to inhibit liver fibrosis and promote its resolution.—Liu, S. B., Ikenaga, N., Peng, Z.‐W., Sverdlov, D. Y., Greenstein, A., Smith, V., Schuppan, D., Popov, Y. Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice. FASEB J. 30, 1599–1609 (2016). www.fasebj.org