Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice

Susan B. Liu, Naoki Ikenaga, Zhen Wei Peng, Deanna Y. Sverdlov, Andrew Greenstein, Victoria Smith, Detlef Schuppan, Yury Popov

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

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 (CCl4)-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.

Original languageEnglish
Pages (from-to)1599-1609
Number of pages11
JournalFASEB Journal
Volume30
Issue number4
DOIs
Publication statusPublished - Apr 1 2016
Externally publishedYes

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Protein-Lysine 6-Oxidase
Aminopropionitrile
Liver Cirrhosis
Liver
Fibrosis
Collagen
Stabilization
Hepatic Stellate Cells
Chemical activation
Carbon Tetrachloride
Macrophages
Stiffness matrix
Transcription
Infiltration
Assays
Reverse Transcription
Cicatrix
Polymerase Chain Reaction
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice. / Liu, Susan B.; Ikenaga, Naoki; Peng, Zhen Wei; Sverdlov, Deanna Y.; Greenstein, Andrew; Smith, Victoria; Schuppan, Detlef; Popov, Yury.

In: FASEB Journal, Vol. 30, No. 4, 01.04.2016, p. 1599-1609.

Research output: Contribution to journalArticle

Liu, Susan B. ; Ikenaga, Naoki ; Peng, Zhen Wei ; Sverdlov, Deanna Y. ; Greenstein, Andrew ; Smith, Victoria ; Schuppan, Detlef ; Popov, Yury. / Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice. In: FASEB Journal. 2016 ; Vol. 30, No. 4. pp. 1599-1609.
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