Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis
Chris J. Weston, … , Christopher P. Day, David H. Adams
Chris J. Weston, … , Christopher P. Day, David H. Adams
Published December 22, 2014
Citation Information: J Clin Invest. 2015;125(2):501-520. https://doi.org/10.1172/JCI73722.
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Research Article Hepatology

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

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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Figure 2

Expression of VAP-1 is increased in liver tissue from patients with evidence of liver disease and localizes to hepatic stromal cells.

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Expression of VAP-1 is increased in liver tissue from patients with evid...
(A) Immunohistochemical detection of VAP-1 (brown) in liver sections taken from patients across the spectrum of NAFLD (mild-to-moderate-to-severe steatosis and cirrhosis). Sections were counterstained with hematoxylin (blue). Scale bars: 50 μm. (B) VAP-1 staining (red) was detected in sinusoids and fibrotic septa in CLD (primary biliary cirrhosis, top panel; primary sclerosing cholangitis, middle panel; and alcoholic liver disease, lower panel). Scale bars: 200 μm. (C) Confocal fluorescence microscopy with dual fluorescent staining for VAP-1 (green) and cell-specific markers in cirrhotic liver (red). VAP-1 was present on some CD31+ endothelial cells, but was predominantly associated with the stromal cell markers α-SMA and CD90. VAP-1 did not colocalize with markers of cholangiocytes (EpCAM) or hepatocytes (CK18). Scale bars: 50 μm. (D) Multicolor confocal microscopy showed increased VAP-1 expression levels (green) in the expanded space of Disse in the sinusoids of NASH livers (lower panel) when compared with levels in normal livers (upper panel). The endothelial marker CD31 is shown in red (coexpression is yellow). Scale bars: 20 μm.