Introduction Vascular Adhesion Protein-1 (VAP-1) is an adhesion molecule and membrane-bound amine oxidase. Our group has previously demonstrated that VAP-1 is able to support lymphocyte recruitment across human hepatic sinusoidal endothelium in vitro. Soluble VAP-1 (sVAP-1) is released into the circulation from adipose tissue and the hepatic vascular bed, has insulin like effects and is capable of inducing and propagating oxidative stress.
Aim To investigate the role of VAP-1 in the progression of steatosis to steatohepatitis and cirrhosis.
Method Human hepatic VAP-1 expression was determined using immunofluorescent labelling and multicolour confocal microscopy. Serum sVAP-1 levels were measured by ELISA in 144 patients with histologically graded NAFLD and 74 controls matched for age and metabolic phenotype. Two murine models of steatohepatitis were studied; (1) a methionine choline deficient diet was administered for 6 weeks in wild-type (WT) mice, WT mice treated with anti-VAP-1 antibody, and VAP-1 null mice (n=6 per group), 2) A western lifestyle model incorporating high trans-fat diet and fructose supplemented drinking water was administered to WT and VAP-1 null mice for 6, 9 and 12 months (n=10 per group). Control animals remained on normal chow. Liver infiltrating lymphocytes were identified and quantified using flow cytometry. Fibrosis was assessed by immunohistochemistry and qRT-PCR for aSMA and collagen I.
Results (1) Human studies: We report increased hepatic expression of VAP-1 in NAFLD associated with elevated serum levels of sVAP-1 compared with controls (946±468 ng/ml vs 265±78 ng/ml, p<0.0001). Multiple regression modelling reveals sVAP-1 to be the best predictor of histological fibrosis in our cohort. We detected strong VAP-1 expression in fibrotic septa co-localised with activated liver myofibroblasts (aLMF). In vitro human aLMF expressed and released sVAP-1 which promoted lymphocyte migration through a novel H2O2-mediated enzyme-dependent mechanism. (2) Experimental steatohepatitis: VAP-1 null and/or antibody treated mice developed fewer inflammatory foci and delayed onset of fibrosis in two murine models of NASH. In both models there was a specific failure to expand the intrahepatic CD4+ and NKT cell populations in VAP-1 null mice compared with 2 to 3-fold increases in WT mice. Three WT animals developed hepatocellular carcinoma by 12 months in the western lifestyle model but no tumours were found in VAP-1 null mice.
Conclusion Our results implicate an important role for VAP-1 in steatohepatitis, in both humans and mice. The ability to target VAP-1 with antibodies or small molecule inhibitors makes it an attractive therapeutic target.
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