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Lookup NU author(s): Professor Quentin AnsteeORCiD, Professor Chris Day
This is the final published version of an article that has been published in its final definitive form by American Society for Clinical Investigation, 2015.
For re-use rights please refer to the publisher's terms and conditions.
Nonalcoholic fatty liver disease (NAFLD) encompasses a range of manifestations, including steatosis and cirrhosis. Progressive disease is characterized by hepatic leukocyte accumulation in the form of steatohepatitis. The adhesion molecule vascular adhesion protein-1 (VAP-1) is a membrane-bound amine oxidase that promotes leukocyte recruitment to the liver, and the soluble form (sVAP-1) accounts for most circulating monoamine oxidase activity, has insulin-like effects, and can initiate oxidative stress. Here, we determined that hepatic VAP-1 expression is increased in patients with chronic liver disease and that serum sVAP-1 levels are elevated in patients with NAFLD compared with those in control individuals. In 4 murine hepatic injury models, an absence or blockade of functional VAP-1 reduced inflammatory cell recruitment to the liver and attenuated fibrosis. Moreover, disease was reduced in animals expressing a catalytically inactive form of VAP-1, implicating enzyme activity in the disease pathogenesis. Within the liver, hepatic stromal cells expressed functional VAP-1, and evaluation of cultured cells revealed that sVAP-1 promotes leukocyte migration through catalytic generation of ROS, which depended on VAP-1 enzyme activity. VAP-1 enhanced stromal cell spreading and wound closure and modulated expression of profibrotic genes. Together, these results link the amine oxidase activity of VAP-1 with hepatic inflammation and fibrosis and suggest that targeting VAP-1 has therapeutic potential for NAFLD and other chronic fibrotic liver diseases.
Author(s): Weston CJ, Shepherd EL, Claridge LC, Rantakari P, Curbishley SM, Tomlinson JW, Hubscher SG, Reynolds GM, Aalto K, Anstee QM, Jalkanen S, Salmi M, Smith DJ, Day CP, Adams DH
Publication type: Article
Publication status: Published
Journal: Journal of Clinical Investigation
Year: 2015
Volume: 125
Issue: 2
Pages: 501-520
Print publication date: 01/02/2015
Online publication date: 22/12/2014
Acceptance date: 13/11/2014
Date deposited: 22/05/2018
ISSN (print): 0021-9738
ISSN (electronic): 1558-8238
Publisher: American Society for Clinical Investigation
URL: http://dx.doi.org/10.1172/JCI73722
DOI: 10.1172/JCI73722
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