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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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 10

Liver tissue from Aoc3–/– animals exhibits reduced steatosis and fibrosis when fed a WLM diet.

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Liver tissue from Aoc3–/– animals exhibits reduced steatosis and fibrosi...
(A) Serum ALT levels of WT or Aoc3–/– animals fed either a NC or WLM diet for 6 or 9 months and Aoc3 expression in WT animals at 9 months. 3–5 animals per group. (B) Collagen deposition in the WLM animals was visualized by Van Gieson’s staining at 9 and 12 months, and the surface area covered by the stain at the 12-month time point was evaluated by ImageJ software (C). 5–6 animals per group; 5 fields per animal. Scale bars: 50 μm. (D) Changes in Acta2 and Col1a1 expression in the liver tissue of these animals at 12 months were quantified by qRT-PCR. 4–6 animals per group. (E and F) The extent of steatosis in WT and Aoc3–/– animals fed a WLM diet at 9 months was evaluated by Oil red O staining and ImageJ software. 4 animal per group; 3–5 fields per animal. Scale bars: 50 μm. ***P < 0.001 and ****P < 0.0001 by Mann-Whitney U test.