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J Hepatol. 2018 Aug;69(2):368-377. doi: 10.1016/j.jhep.2018.04.009. Epub 2018 Apr 28.

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

Author information

1
Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria; Institute of Pathology, Medical University of Graz, Austria.
2
Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria.
3
Gilead Sciences, Foster City, CA, USA.
4
Division of Gastroenterology and Hepatology, University of California Davis School of Medicine Davis, CA, USA.
5
Institute of Pathology, Medical University of Graz, Austria.
6
Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria.
7
Norwegian PSC Research Center, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet and Institute of Clinical Medicine, University of Oslo, Norway.
8
BioMérieux SA, Marcy l'Etoile, France.
9
Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria; Department of Internal Medicine, Medical University of Graz, Austria.
10
Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
11
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria.
12
Department of Internal Medicine, Medical University of Graz, Austria.
13
Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
14
Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria; Department of Internal Medicine, Medical University of Graz, Austria. Electronic address: peter.fickert@medunigraz.at.

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.

KEYWORDS:

Cholangiopathy; Epithelial barrier function; Liver fibrosis; Lysyl oxidases; Primary sclerosing cholangitis; Tight junction

PMID:
29709678
DOI:
10.1016/j.jhep.2018.04.009

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