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 4

VAP-1 contributes to scar formation in CCl4-induced murine fibrosis.

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VAP-1 contributes to scar formation in CCl4-induced murine fibrosis. (A)...
(A) Picrosirius red staining of liver from WT mice receiving an 8-week treatment of MO, CCl4, or CCl4 plus a function–blocking anti–VAP-1 Ab (WT CCl4 + Ab) or liver from Aoc3–/– mice that received CCl4 (Aoc3–/– CCl4). Lower panels depict the same experimental groups following an additional 4 weeks of resolution after stopping CCl4 at 8 weeks. Scale bars: 200 μm. (B) Serum ALT levels and (C and D) sirius red (C) and α-SMA (D) staining following 8 weeks of vehicle or CCl4 administration (white bars) and 8 weeks of treatment followed by 4-week resolution (black bars). Fibrosis was also determined by qRT-PCR for Col1a1 and Acta2 (E and F). 3–4 animals per group. 1-way ANOVA with Tukey’s post-hoc test: *P < 0.05, **P < 0.01 and ***P < 0.001 versus WT MO at 8 weeks; †P < 0.05 and #P < 0.001 versus WT MO at 12 weeks.