Journal Article

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

Tomlinson, Jeremy W., Adams, David H., Smith, David J., Salmi, Marko, Anstee, Quentin M., Shepherd, Emma L., Aalto, Kristiina, Jalkanen, Sirpa, Reynolds, Gary M., Curbishley, Stuart M., Claridge, Lee C., Rantakari, Pia, Day, Christopher P., Weston, Chris J., Hubscher, Stefan G.

2015

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adhesion / Adult / Age / Amine Oxidase (Copper-Containing) - blood / Animals / Biomedical research / Cell adhesion molecules / Cell Adhesion Molecules - blood / Cell Line / Cell Movement / Chronic Disease / Cohort Studies / Development and progression / Diabetes / Disease Models, Animal / Endothelium / Female / Free radicals / Gene Expression Regulation, Enzymologic / Genetic aspects / Genotype & phenotype / Hepatitis - enzymology / Hepatitis - pathology / Hepatitis - therapy / Humans / Inflammation - enzymology / Inflammation - pathology / Inflammation - therapy / Insulin resistance / Leukocytes - enzymology / Leukocytes - pathology / Liver cirrhosis / Liver Cirrhosis - enzymology / Liver Cirrhosis - pathology / Liver Cirrhosis - therapy / Liver diseases / Male / Metabolism / Mice / Mice, Knockout / Middle Aged / Monoamine oxidase / Non-alcoholic Fatty Liver Disease - enzymology / Non-alcoholic Fatty Liver Disease - pathology / Non-alcoholic Fatty Liver Disease - therapy / Oxidative Stress / Physiological aspects / Properties / Reactive Oxygen Species - metabolism / Rodents / Software