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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

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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.

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 1

Serum sVAP-1 is elevated in patients with NAFLD and correlates with histological markers of liver injury.

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Serum sVAP-1 is elevated in patients with NAFLD and correlates with hist...
(A) sVAP-1 levels in patients with NAFLD (n = 133) were compared with those in a control cohort of patients with metabolic syndrome but no evidence of liver injury (n = 74). (B–E) Elevated sVAP-1 levels in patients with NAFLD were associated with lobular inflammation (B), hepatocyte ballooning (C), fibrosis (D), and NASH (E). (F) sVAP-1 concentrations in patient serum increased with the fibrosis stage as determined from biopsy samples (Kleiner classification). (A–E) P values were calculated by Mann-Whitney U test; (F) Kruskal-Wallis test (P = 0.0003) and Cuzick trend test (P ≤ 0.0001); P’ was calculated by Mann-Whitney U test with Bonferroni’s correction.
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