title: Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis.
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.forename: Chris J
authors.initials: CJ
authors.lastname: Weston
authors.forename: Emma L
authors.initials: EL
authors.lastname: Shepherd
authors.forename: Lee C
authors.initials: LC
authors.lastname: Claridge
authors.forename: Pia
authors.initials: P
authors.lastname: Rantakari
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Curbishley
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Tomlinson
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Hubscher
authors.forename: Gary M
authors.initials: GM
authors.lastname: Reynolds
authors.forename: Kristiina
authors.initials: K
authors.lastname: Aalto
authors.forename: Quentin M
authors.initials: QM
authors.lastname: Anstee
authors.forename: Sirpa
authors.initials: S
authors.lastname: Jalkanen
authors.forename: Marko
authors.initials: M
authors.lastname: Salmi
authors.forename: David J
authors.initials: DJ
authors.lastname: Smith
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Day
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
mesh_terms: D000328:Adult; D006631:Amine Oxidase (Copper-Containing) / Q000097:blood*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000097:blood*; D002460:Cell Line; D002465:Cell Movement; D002908:Chronic Disease; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006505:Hepatitis / Q000201:enzymology / Q000473:pathology / Q000628:therapy; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000473:pathology / Q000628:therapy; D007962:Leukocytes / Q000201:enzymology* / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000201:enzymology* / Q000473:pathology / Q000628:therapy; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D017382:Reactive Oxygen Species; C076668:AOC3 protein, human; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse