scholarly journals Inhibition of vascular adhesion protein-1 modifies hepatic steatosis in vitro and in vivo

2020 ◽  
Vol 12 (11) ◽  
pp. 931-948
Author(s):  
Emma L Shepherd ◽  
Sumera Karim ◽  
Philip N Newsome ◽  
Patricia F Lalor
Keyword(s):  
Hepatic Steatosis ◽  
Adhesion Protein ◽  
Vascular Adhesion ◽  
Vascular Adhesion Protein 1

scholarly journals Vascular Adhesion Protein 1 Mediates Gut Microbial Flagellin-Induced Inflammation, Leukocyte Infiltration, and Hepatic Steatosis

Sci ◽  
2021 ◽  
Vol 3 (1) ◽  
pp. 13
Author(s):  
Raine Toivonen ◽  
Sanja Vanhatalo ◽  
Maija Hollmén ◽  
Eveliina Munukka ◽  
Anniina Keskitalo ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Hepatic Steatosis ◽  
Visceral Adipose Tissue ◽  
Leukocyte Infiltration ◽  
Fat Accumulation ◽  
Adhesion Protein ◽  
Hepatic Fat ◽  
Vascular Adhesion ◽  
Visceral Adipose ◽  
Vascular Adhesion Protein 1

Toll-like receptor 5 ligand, flagellin, and vascular adhesion protein 1 (VAP-1) are involved in non-alcoholic fatty liver disease. This study aimed to determine whether VAP-1 mediates flagellin-induced hepatic fat accumulation. The effects of flagellin on adipocyte VAP-1 expression were first studied in vitro. Then, flagellin (100 ng/mouse) or saline was intraperitoneally injected into C57BL/6J (WT) and C57BL/6-Aoc3-/- (VAP-1 KO) mice on a high-fat diet twice a week every 2 weeks for 10 weeks. After that, the effects on inflammation, insulin signaling, and metabolism were studied in liver and adipose tissues. Hepatic fat was quantified histologically and biochemically. Because flagellin challenge increased VAP-1 expression in human adipocytes, we used VAP-1 KO mice to determine whether VAP-1 regulates the inflammatory and metabolic effects of flagellin in vivo. In mice, VAP-1 mediated flagellin-induced inflammation, leukocyte infiltration, and lipolysis in visceral adipose tissue. Consequently, an increased release of glycerol led to hepatic steatosis in WT, but not in KO mice. Flagellin-induced hepatic fibrosis was not mediated by VAP-1. VAP-1 KO mice harbored more inflammation-related microbes than WT mice, while flagellin did not affect the gut microbiota. Our results suggest that by acting on visceral adipose tissue, flagellin increased leukocyte infiltration that induced lipolysis. Further, the released glycerol participated in hepatic fat accumulation. In conclusion, the results describe that gut microbial flagellin through VAP-1 induced hepatic steatosis.

scholarly journals In Vivo Detection of Vascular Adhesion Protein-1 in Experimental Inflammation

2000 ◽  
Vol 157 (2) ◽  
pp. 463-471 ◽  
Author(s):  
Kimmo Jaakkola ◽  
Tuomo Nikula ◽  
Riikka Holopainen ◽  
Tommi Vähäsilta ◽  
Marja-Terttu Matikainen ◽  
...  
Keyword(s):  
Adhesion Protein ◽  
In Vivo Detection ◽  
Experimental Inflammation ◽  
Vascular Adhesion ◽  
Vascular Adhesion Protein 1

scholarly journals Induction and function of vascular adhesion protein-1 at sites of inflammation.

1993 ◽  
Vol 178 (6) ◽  
pp. 2255-2260 ◽  
Author(s):  
M Salmi ◽  
K Kalimo ◽  
S Jalkanen
Keyword(s):  
Cell Types ◽  
Endothelial Lining ◽  
High Endothelial Venules ◽  
Adhesion Protein ◽  
Endothelial Adhesion Molecule ◽  
Vascular Adhesion ◽  
And Function ◽  
Lymphatic Organs ◽  
Vascular Adhesion Protein 1

Emigration of leukocytes from the blood into the tissues is critical in controlling lymphocyte patrolling in different lymphatic organs and in leukocyte accumulation at sites of inflammation. During the first stage of the extravasation process, leukocytes bind to the endothelial lining of vessels. At the molecular level, several adhesion molecules on leukocytes and endothelial cells function as receptor-ligand pairs in mediating this dynamic interaction. Recently, we have identified a novel human endothelial cell molecule, vascular adhesion protein 1 (VAP-1), that mediates lymphocyte binding (Salmi, M., and S. Jalkanen. 1992. Science [Wash. DC] 257:1407). VAP-1 was initially characterized by mAb 1B2 which inhibits lymphocyte adhesion to high endothelial venules (HEV) and to purified VAP-1 protein. Here we report the location and function of VAP-1 in normal and inflamed tissues in humans. VAP-1 is abundant in HEV of lymphatic organs belonging to the peripheral lymph node system, but considerably less is expressed in vessels of mucosa-associated lymphatic tissues. A subset of venules in most normal nonlymphatic tissues like skin, brain, kidney, liver, and heart is also VAP-1 positive. In addition to vessels, VAP-1 is distributed on a few other cell types, most notably in dendritic-like cells of germinal centers. At sites of inflammation, such as in inflammatory bowel diseases and chronic dermatoses, expression of VAP-1 is clearly increased. The induced VAP-1 is functional, since mAb 1B2 inhibits lymphocyte binding to inflamed lamina propria venules by approximately 60%. Thus VAP-1 is an endothelial adhesion molecule that under normal conditions is expressed mainly in HEV of lymphatic tissues. However, expression of functional VAP-1 in vivo is upregulated during an inflammatory reaction at other sites as well. Inducibility of VAP-1 suggests that it may play a significant role, not only in recirculation of lymphocytes, but also in controlling entry of leukocytes into sites of inflammation.

scholarly journals Comparison of Inhibitor and Substrate Selectivity between Rodent and Human Vascular Adhesion Protein-1

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Ryo Kubota ◽  
Michael J. Reid ◽  
Kuo Lee Lieu ◽  
Mark Orme ◽  
Christine Diamond ◽  
...  
Keyword(s):  
Amine Oxidase ◽  
Leukocyte Adhesion ◽  
Primary Amines ◽  
Oxidative Deamination ◽  
Adhesion Protein ◽  
Common Marker ◽  
Small Primary ◽  
Vascular Adhesion ◽  
Vascular Adhesion Protein 1

Vascular adhesion protein-1 (VAP-1) is an ectoenzyme that functions as a copper-containing amine oxidase and is involved in leukocyte adhesion at sites of inflammation. Inhibition of VAP-1 oxidative deamination has become an attractive target for anti-inflammatory therapy with demonstrated efficacy in rodent models of inflammation. A previous comparison of purified recombinant VAP-1 from mouse, rat, monkey, and human gene sequences predicted that rodent VAP-1 would have higher affinity for smaller hydrophilic substrates/inhibitors because of its narrower and more hydrophilic active site channel. An optimized in vitro oxidative deamination fluorescence assay with benzylamine (BA) was used to compare inhibition of five known inhibitors in recombinant mouse, rat, and human VAP-1. Human VAP-1 was more sensitive compared to rat or mouse VAP-1 (lowest IC50 concentration) to semicarbazide but was least sensitive to hydralazine and LJP-1207. Hydralazine had a lower IC50 in rats compared to humans, although not significant. However, the IC50 of hydralazine was significantly higher in the rat compared to mouse VAP-1. The larger hydrophobic compounds from Astellas (compound 35c) and Boehringer Ingelheim (PXS-4728A) were hypothesized to have higher binding affinity for human VAP-1 compared to rodent VAP-1 since the channel in human VAP-1 is larger and more hydrophobic than that in rodent VAP-1. Although the sensitivity of these two inhibitors was the lowest in the mouse enzyme, we found no significant differences between mouse, rat, and human VAP-1. Michaelis-Menten kinetics of the small primary amines phenylethylamine and tyramine were also compared to the common marker substrate BA demonstrating that BA had the highest affinity among the substrates. Rat VAP-1 had the highest affinity for all three substrates and mouse VAP-1 had intermediate affinity for BA and phenylethylamine, but tyramine was not a substrate for mouse VAP-1 under these assay conditions. These results suggest that comparing oxidative deamination in mouse and rat VAP-1 may be important if using these species for preclinical efficacy models.

scholarly journals Vascular Adhesion Protein 1 Mediates Gut Microbial Flagellin-Induced Inflammation, Leukocyte Infiltration, and Hepatic Steatosis

Sci ◽  
2019 ◽  
Vol 1 (3) ◽  
pp. 65 ◽  
Author(s):  
Toivonen ◽  
Vanhatalo ◽  
Hollmén ◽  
Munukka ◽  
Keskitalo ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Hepatic Steatosis ◽  
Visceral Adipose Tissue ◽  
Leukocyte Infiltration ◽  
Fat Accumulation ◽  
Adhesion Protein ◽  
Hepatic Fat ◽  
Vascular Adhesion ◽  
Visceral Adipose ◽  
Vascular Adhesion Protein 1

Toll-like receptor 5 ligand, flagellin, and Vascular Adhesion Protein-1 (VAP-1) are involved in non-alcoholic fatty liver disease (NAFLD). This study aimed to determine whether VAP-1 mediates flagellin-induced hepatic fat accumulation. The effects of flagellin on adipocyte VAP-1 expression were first studied in vitro. Then, flagellin (100 ng/mouse) or saline was intraperitoneally injected to C57BL/6J WT and C57BL/6-Aoc3-/- (VAP-1 KO) mice on high-fat diet twice a week every two weeks for 10-weeks. After that, the effects on inflammation, insulin signaling, and metabolism were studied in liver and adipose tissues. Hepatic fat was quantified histologically and biochemically. Because flagellin challenge increased VAP-1 expression in human adipocytes, we used VAP-1 KO mice to determine whether VAP-1 regulates the inflammatory and metabolic effects of flagellin in vivo. In mice, VAP-1 mediated flagellin-induced inflammation, leukocyte infiltration and lipolysis in visceral adipose tissue. Consequently, increased release of glycerol led to hepatic steatosis in WT but not KO mice. Flagellin-induced hepatic fibrosis was not mediated by VAP-1. VAP-1 KO mice harbored more inflammation-related microbes than WT, while flagellin did not affect the gut microbiota. Our results suggest that by acting on visceral adipose tissue, flagellin increased leukocyte infiltration that induced lipolysis. Further, the released glycerol participated in hepatic fat accumulation. In conclusion, the results describe that gut microbial flagellin through VAP-1 induced hepatic steatosis.

The oxidase activity of vascular adhesion protein-1 (VAP-1) induces endothelial E- and P-selectins and leukocyte binding

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 1864-1870 ◽  
Author(s):  
Sirpa Jalkanen ◽  
Marika Karikoski ◽  
Nathalie Mercier ◽  
Kaisa Koskinen ◽  
Tiina Henttinen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymphoid Tissues ◽  
High Endothelial Venules ◽  
Adhesion Protein ◽  
A Cell ◽  
Vascular Adhesion ◽  
Activity Dependent ◽  
Oxidase Reaction ◽  
Vascular Adhesion Protein 1

Abstract Leukocyte migration from the blood into tissues is pivotal in immune homeostasis and in inflammation. During the multistep extravasation cascade, endothelial selectins (P- and E-selectin) and vascular adhesion protein-1 (VAP-1), a cell-surface–expressed oxidase, are important in tethering and rolling. Here, we studied the signaling functions of the catalytic activity of VAP-1. Using human endothelial cells transfected with wild-type VAP-1 and an enzymatically inactive VAP-1 point mutant, we show that transcription and translation of E- and P-selectins are induced through the enzymatic activity of VAP-1. Moreover, use of VAP-1–deficient animals and VAP-1–deficient animals carrying the human VAP-1 as a transgene show a VAP-enzyme activity–dependent induction of P-selectin in vivo. Up-regulation of P-selectin was found both in high endothelial venules in lymphoid tissues and in flat-walled vessels in noninflamed tissues. VAP-1 activity in vivo led to increased P-selectin–dependent binding of lymphocytes to endothelial cells. These data show that the oxidase reaction catalyzed by VAP-1 alters the expression of other molecules involved in the leukocyte extravasation cascade. Our findings indicate cross-talk between adhesion molecules involved in the tethering and rolling of leukocytes and show that VAP-1–dependent signaling can prime the vessels for an enhanced inflammatory response.

Vascular adhesion protein 1 (VAP‐1) functions as a molecular brake during granulocyte rolling and mediates recruitment in vivo

2001 ◽  
Vol 15 (2) ◽  
pp. 373-382 ◽  
Author(s):  
SAMI TOHKA ◽  
MARJA‐LEENA LAUKKANEN ◽  
SIRPA JALKANEN ◽  
MARKO SALMI
Keyword(s):  
Adhesion Protein ◽  
Vascular Adhesion ◽  
Molecular Brake ◽  
Vascular Adhesion Protein 1
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