Vascular adhesion protein-1 and liver disease progression
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder and is associated with metabolic dysfunction. Persistent hepatic inflammation in diseased livers results in progressive fibrosis and loss of hepatic function. Vascular adhesion protein-1 (VAP-1) is expressed on the hepatic endothelium and recruits leukocytes to the liver; however, it is also produced as a soluble form (sVAP-1) that has monoamine oxidase activity. In this episode, David Adams, Chris Weston, and Emma Shepherd discuss their work, which links sVAP-1 levels in patient serum to NAFLD severity and prognosis. In murine hepatic injury models, loss of VAP-1 or inhibition of VAP-1 enzymatic function reduced inflammatory cell recruitment to the liver and fibrosis. The results of this study suggest that targeting VAP-1 has potential as a therapeutic strategy for limiting hepatic inflammation and 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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