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Open AccessArticlePost Publication Peer ReviewVersion 1, Original

Vascular Adhesion Protein 1 Mediates Gut Microbial Flagellin-Induced Inflammation, Leukocyte Infiltration, and Hepatic Steatosis (Version 1, Original)

Institute of Biomedicine, Faculty of Medicine, University of Turku, 20014 Turku, Finland
Medicity Research Laboratory, University of Turku, 20014 Turku, Finland
Department of Clinical Microbiology and Immunology, Turku University Hospital, 20521 Turku, Finland
Turku Centre for Biotechnology, of Turku, 20014 Turku, Finland
Faculty of Sport and Health Sciences, University of Jyväskylä, 40014 Jyväskylä, Finland
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Received: 7 November 2019 / Accepted: 26 November 2019 / Published: 16 December 2019
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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. View Full-Text
Keywords: gut microbiota; liver; metabolism; inflammation gut microbiota; liver; metabolism; inflammation
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Toivonen, R.; Vanhatalo, S.; Hollmén, M.; Munukka, E.; Keskitalo, A.; Pietilä, S.; Elo, L.; Huovinen, P.; Jalkanen, S.; Pekkala, S. Vascular Adhesion Protein 1 Mediates Gut Microbial Flagellin-Induced Inflammation, Leukocyte Infiltration, and Hepatic Steatosis. Sci 2019, 1, 65.

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