Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis
Chris J. Weston, … , Christopher P. Day, David H. Adams
Chris J. Weston, … , Christopher P. Day, David H. Adams
Published December 22, 2014
Citation Information: J Clin Invest. 2015;125(2):501-520. https://doi.org/10.1172/JCI73722.
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Research Article Hepatology

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

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.

Authors

Chris J. Weston, Emma L. Shepherd, Lee C. Claridge, Pia Rantakari, Stuart M. Curbishley, Jeremy W. Tomlinson, Stefan G. Hubscher, Gary M. Reynolds, Kristiina Aalto, Quentin M. Anstee, Sirpa Jalkanen, Marko Salmi, David J. Smith, Christopher P. Day, David H. Adams

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Figure 6

WT mice receiving anti–VAP-1 Ab (BTT-1029) and Aoc3–/– animals are protected against MCD diet–induced steatohepatitis.

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WT mice receiving anti–VAP-1 Ab (BTT-1029) and Aoc3–/– animals are prote...
(A) Serum ALT levels of animals fed an MCD diet. (B and C) Inflammatory score based on sections stained with H&E, determined as: 0 = no foci per field, 1 = 1–2 foci, 2 = 3–4 foci, 3 = >4 foci. 5 fields of view per animal. Scale bars: 50 μm. (D) Accumulation of lipid droplets in murine tissue sections was assessed by Oil red O staining (red) with hematoxylin counterstaining (blue) and expressed as a percentage of surface area occupied by the lipid (E, 5 fields of view per animal). 6 animals per group. Scale bars: 50 μm. ****P < 0.0001 by 1-way ANOVA with Tukey’s post-hoc test (A and E) and ***P < 0.001 by Kruskal-Wallis test with Dunn’s multiple comparisons (C).