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

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number73722
Pages (from-to)501-520
Number of pages20
JournalJournal of Clinical Investigation
Issue number2
Publication statusPublished - 2 Feb 2015


  • Adult
  • Amine Oxidase (Copper-Containing)/blood
  • Animals
  • Cell Adhesion Molecules/blood
  • Cell Line
  • Cell Movement
  • Chronic Disease
  • Cohort Studies
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Enzymologic
  • Hepatitis/enzymology
  • Humans
  • Inflammation/enzymology
  • Leukocytes/enzymology
  • Liver Cirrhosis/enzymology
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Non-alcoholic Fatty Liver Disease/enzymology
  • Oxidative Stress
  • Reactive Oxygen Species/metabolism


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