Vascular Adhesion Protein 1 Mediates Gut Microbial Flagellin-Induced Inflammation, Leukocyte Infiltration, and Hepatic Steatosis
Toivonen, R., Vanhatalo, S., Hollmén, M., Munukka, E., Keskitalo, A., Pietilä, S., Elo, L., Huovinen, P., Jalkanen, S., & Pekkala, S. (2021). Vascular Adhesion Protein 1 Mediates Gut Microbial Flagellin-Induced Inflammation, Leukocyte Infiltration, and Hepatic Steatosis. Sci, 3(1), Article 13. https://doi.org/10.3390/sci3010013
© 2021 the Authors
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. ...
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Related funder(s)Academy of Finland
Funding program(s)Postdoctoral Researcher, AoF
Additional information about fundingThis study was financially supported by the Academy of Finland postdoctoral research fellowships for Raine Toivonen (285503) and Satu Pekkala (267719), by the Academy of Finland Researcher fellowship for Satu Pekkala (308042) and by the Academy Professorship for Sirpa Jalkanen (272239). In addition, funding was granted to Satu Pekkala by the Finnish Diabetes Research Foundation, by the Finnish Culture Foundation and by the Finnish Instrumentarium Research Foundation. ...
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