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

Research output: Contribution to journalArticle

Authors

  • Lee C Claridge
  • Pia Rantakari
  • Gary M Reynolds
  • Kristiina Aalto
  • Quentin M Anstee
  • Sirpa Jalkanen
  • Marko Salmi
  • David J Smith
  • Christopher P Day
  • David Adams

External organisations

  • BIOTIE THERAPIES CORPORATION

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.

Details

Original languageEnglish
Pages (from-to)501-20
Number of pages20
JournalJournal of Clinical Investigation
Volume125
Issue number2
Publication statusPublished - Feb 2015