Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice
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 (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
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LOX inhibition destabilizes collagen fibers and accelerates fibrosis regression in chemically-induced fibrosis.
“LOX inhibition destabilizes collagen fibers and accelerates fibrosis regression in chemically-induced fibrosis (273), however clinical trials of a neutralizing antibody to lysyl oxidase like 2 (LOXL2) had no effect (280).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [273]
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References 31 · Cited by 224
- Authors
- Liu, S. B., Ikenaga, N., Peng, Z., Sverdlov, D. Y., Greenstein, A., Smith, V., Schuppan, D., & Popov, Y.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Division of Gastroenterology and Hepatology Beth Israel Deaconess Medical Center, Harvard Medical School Boston Massachusetts USA
- Gilead Sciences (United States) (US)
- Corresponding author
- Popov, Yury
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2015-12-23
- Volume
- 30
- Issue
- 4
- Pages
- 1599-1609
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2256440089
- Cited by
- 224
- References
- 31
- Citations by year
- 2026: 14 · 2025: 15 · 2024: 21 · 2023: 25 · 2022: 26 · 2021: 22 · 2020: 30 · 2019: 22 · 2018: 30 · 2017: 11 · 2016: 6
- FWCI
- 9.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- lysyl oxidase, liver fibrosis, collagen cross-linking, collagen stabilization, fibrosis reversal, beta-aminopropionitrile, hepatic stellate cells, carbon tetrachloride-induced fibrosis, fibrosis resolution
- MeSH terms
- Collagen Type I, alpha 1 Chain, Aminopropionitrile, Animals, Carbon Tetrachloride, Collagen, Fibrosis, Injections, Intraperitoneal, Liver, Liver Cirrhosis, Experimental, Protein-Lysine 6-Oxidase, Macrophages, Male, Mice, Inbred C57BL, Gene Expression, Disease Progression, Microscopy, Confocal, Tissue Inhibitor of Metalloproteinase-1, Reverse Transcriptase Polymerase Chain Reaction, Collagen Type I, Matrix Metalloproteinase 13, Transforming Growth Factor beta1, Hepatic Stellate Cells
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