Cited by 39Liver Diseases and ImmunityLiver physiology and pathologyDrug Transport and Resistance Mechanisms

Lysyl oxidase-like protein 2 (LOXL2) modulates barrier function in cholangiocytes in cholestasis

Pollheimer, Marion J., Racedo, Silvia, Mikels-Vigdal, Amanda, Marshall, Derek, Bowlus, Christopher, Lackner, Carolin, Madl, Tobias, Karlsen, Tom H. +13 more·2018·Journal of Hepatology

Abstract

Background & aims The lysyl oxidase-like protein 2 (LOXL2) promotes stabilization of the extracellular matrix, chemotaxis, cell growth and cell mobility. We aimed to (i) identify stimuli of LOXL2 in cholangiopathies, (ii) characterize the effects of LOXL2 on biliary epithelial cells' (BECs) barrier function, (iii) compare LOXL2 expression in primary sclerosing cholangitis (PSC), primary biliary cholangitis, and disease controls, and (iv) to determine LOXL2 expression and its cellular sources in four mouse models of cholangiopathies.Methods Cultured murine BECs were challenged with well-known triggers of cellular senescence, hypoxia, phospholipid-deficient Abcb4-/- mouse bile and chenodeoxycholic acid and investigated for LOXL2, SNAIL1 and E-cadherin expression and transepithelial electrical resistance with and without LOX-inhibition. In vivo, LOXL2 expression was studied in PSC livers, and controls and mouse models. We compared LOXL2 serum levels in patients with PSC, secondary SC, primary biliary cholangitis, and controls.Results Cellular senescence, hypoxia, Abcb4-/- bile and chenodeoxycholic acid induced LOXL2 and SNAIL1 expression, repressed E-cadherin expression, and significantly reduced transepithelial electrical resistance in BECs. Notably, all of the pathological changes could be recovered via pharmacological LOX-inhibition. Mouse models showed induced LOXL2 expression in the portal region and in association with ductular reaction. LOXL2 serum levels were significantly elevated in patients with cholangiopathies. In PSC, LOXL2 expression was located to characteristic periductal onion skin-type fibrosis, ductular reaction, Kupffer cells, and fibrotic septa. Importantly, in PSC, LOXL2 overexpression was paralleled by E-cadherin loss in BECs from medium-sized bile ducts.Conclusions Reactive BECs produce LOXL2, resulting in increased tight junction permeability, which can be ameliorated by pharmacological LOX-inhibition in vitro. Reactive BECs, portal myofibroblasts, and Kupffer cells are the main sources of LOXL2 in cholangiopathies.Lay summary In this study, we investigate the role of lysyl oxidase-like protein 2 (LOXL2), an enzyme pivotal in the development of organ fibrosis, in the pathogenesis of cholangiopathies (diseases of bile ducts), such as primary sclerosing cholangitis. We found LOXL2 to be expressed in association with bile duct epithelial injury and uncovered mechanisms for its upregulation and the subsequent effects in vitro and in vivo. Our findings support testing of anti-LOXL2 treatment strategies for patients with primary sclerosing cholangitis.

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Crossref · 10.1016/j.jhep.2018.04.009

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  • Simtuzumab is a humanised monoclonal antibody against LOXL2.

    “Simtuzumab is a humanised monoclonal antibody against lysyl oxidase-like 2 (LOXL2), which has raised much hope for treatment of fibrosis in both NASH and PSC, since LOXL2 contributes to fibrogenesis by cross-linkage of collagen and regulates bile duct permeability.225 226”
  • In patients with PSC and NASH, increased serum levels of LOXL2 correlate with more advanced fibrosis and severity of portal hypertension.

    “In patients with PSC and NASH increased serum levels of LOXL2 correlate with more advanced fibrosis and severity of portal hypertension.226 227”

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Authors
Pollheimer, M. J., Racedo, S., Mikels-Vigdal, A., Marshall, D., Bowlus, C., Lackner, C., Madl, T., Karlsen, T. H., Hov, J. R., Lyman, S. K., Adamkewicz, J., Smith, V., Moreau, E., Zollner, G., Eide, T. J., Stojakovic, T., Scharnagl, H., Gruber, H.-J., Stauber, R. E., Trauner, M., & Fickert, P.
Affiliations
  • Medical University of Graz (AT)
  • Gilead Sciences (United States) (US)
  • University of California, Davis (US)
  • Oslo University Hospital (NO)
  • bioMérieux (France) (FR)
  • Medical University of Vienna (AT)
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2018-08
Volume
69
Issue
2
Pages
368-377
ISSN
0168-8278 (ISSN-L)
OpenAlex
W2801102515
Cited by
38
References
42
Citations by year
2026: 2 · 2025: 2 · 2024: 4 · 2023: 9 · 2022: 4 · 2021: 4 · 2020: 5 · 2019: 5 · 2018: 3
FWCI
2.82
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Hepatology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
cholangiopathy, cholestasis, cholangiocytes, barrier function, tight junction permeability, primary sclerosing cholangitis, primary biliary cirrhosis, secondary sclerosing cholangitis, E-cadherin, SNAI1, chenodeoxycholic acid, bile, extracellular matrix, fibrosis, ductular reaction, Kupffer cells, myofibroblasts, serum biomarkers
MeSH terms
Amino Acid Oxidoreductases, Animals, Biliary Tract, Biliary Tract Diseases, Cells, Cultured, Cholestasis, Disease Models, Animal, Epithelial Cells, Cadherins, Cellular Senescence, Cell Proliferation, Mice

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