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Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis

Lookup NU author(s): Professor Quentin Anstee, Professor Chris Day

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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.

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Abstract

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.


Publication metadata

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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