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

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Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis. / Weston, Chris J; Shepherd, Emma L; Claridge, Lee C; Rantakari, Pia; Curbishley, Stuart; Tomlinson, Jeremy W; Hubscher, Stefan G; Reynolds, Gary M; Aalto, Kristiina; Anstee, Quentin M; Jalkanen, Sirpa; Salmi, Marko; Smith, David J; Day, Christopher P; Adams, David.

In: Journal of Clinical Investigation, Vol. 125, No. 2, 02.2015, p. 501-20.

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Weston, Chris J ; Shepherd, Emma L ; Claridge, Lee C ; Rantakari, Pia ; Curbishley, Stuart ; Tomlinson, Jeremy W ; Hubscher, Stefan G ; Reynolds, Gary M ; Aalto, Kristiina ; Anstee, Quentin M ; Jalkanen, Sirpa ; Salmi, Marko ; Smith, David J ; Day, Christopher P ; Adams, David. / Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 2. pp. 501-20.

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@article{4cde628160964ff28d1c6c6038049cb4,
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.",
author = "Weston, {Chris J} and Shepherd, {Emma L} and Claridge, {Lee C} and Pia Rantakari and Stuart Curbishley and Tomlinson, {Jeremy W} and Hubscher, {Stefan G} and Reynolds, {Gary M} and Kristiina Aalto and Anstee, {Quentin M} and Sirpa Jalkanen and Marko Salmi and Smith, {David J} and Day, {Christopher P} and David Adams",
year = "2015",
month = "2",
doi = "10.1172/JCI73722",
language = "English",
volume = "125",
pages = "501--20",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "2",

}

RIS

TY - JOUR

T1 - Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis

AU - Weston, Chris J

AU - Shepherd, Emma L

AU - Claridge, Lee C

AU - Rantakari, Pia

AU - Curbishley, Stuart

AU - Tomlinson, Jeremy W

AU - Hubscher, Stefan G

AU - Reynolds, Gary M

AU - Aalto, Kristiina

AU - Anstee, Quentin M

AU - Jalkanen, Sirpa

AU - Salmi, Marko

AU - Smith, David J

AU - Day, Christopher P

AU - Adams, David

PY - 2015/2

Y1 - 2015/2

N2 - 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.

AB - 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.

U2 - 10.1172/JCI73722

DO - 10.1172/JCI73722

M3 - Article

C2 - 25562318

VL - 125

SP - 501

EP - 520

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 2

ER -