期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 125, 期 2, 页码 501-520出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI73722
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资金
- Wellcome Trust [083684/Z/07/Z, 091019/Z/09/Z]
- Finnish Academy
- Wellcome Trust [091019/Z/09/Z, 083684/Z/07/Z] Funding Source: Wellcome Trust
- MRC [G0300101, G0700301, G0400496] Funding Source: UKRI
- Medical Research Council [G0802765, G0300101, G0400496, G0700301] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10080] Funding Source: researchfish
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.
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