Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome, and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner

Palak Trivedi, Joseph Tickle, Mette Vesterhus, Peter Eddowes, Tony Bruns, Jani Vainio, Richard Parker, David Smith, Evaggelia Liaskou, Liv Wenche Thorbjornsen, Gideon Hirschfield, Kaisa Auvinen, Stefan Hubscher, Marko Salmi, David Adams, Christopher Weston

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25 Citations (Scopus)
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Abstract

Objective: Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD), wherein aberrant trafficking of mucosal T-cells from the gut is proposed to drive liver injury. Integral to this process is the ectoenzyme vascular adhesion protein (VAP)-1, which through its amine oxidase activity up-regulates mucosal addressin cell adhesion molecule (MAdCAM)-1 expression on hepatic endothelial vasculature, promoting recruitment of gut-tropic (7+) lymphocytes to the liver. Design: We examined VAP-1 expression in PSC patients, correlated levels with clinical characteristics, and determined the functional consequences of enzyme activation through varying substrate provision. Results: The intrahepatic enzyme activity of VAP-1 was elevated in PSC vs. immune-mediated disease controls and non-diseased liver (p<0.001), and adhesion of gut-tropic 7+ lymphocytes to hepatic endothelial cells under flow was attenuated by 50% following administration of the VAP-1 inhibitor semicarbazide (p<0.01). The natural substrate with highest VAP-1 efficiency (enzymatic rate) and efficacy (ability to induce functional MAdCAM-1 expression) was cysteamine – an amine known to be secreted by gut bacteria and colonic epithelium, capable of inducing colitis in mice. Elevated sVAP-1 levels predicted significantly worse transplant-free survival in PSC patients, independently (hazard ratio [HR]: 3.85, p=0.003) and additively (HR: 2.02, p=0.012) of the presence of liver cirrhosis. Conclusion: VAP-1 expression is heightened in PSC, facilitates adhesion of gut-tropic lymphocytes to liver endothelium in a substrate-dependent manner, and levels of the circulating form predict clinical outcome.
Original languageEnglish
JournalGut
Early online date20 Apr 2017
DOIs
Publication statusE-pub ahead of print - 20 Apr 2017

Keywords

  • VAP-1
  • Primary sclerosing cholangitis
  • Lymphocytes

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