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ID 55278
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Horiuchi, Takahiro Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University
Sakata, Natsumi Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University
Narumi, Yoshihiro Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University
Kimura, Tomohiro Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University
Hayashi, Takashi Biomedical Technology Research Center, Tokushima Research Institute
Nagano, Keisuke First Institute of New Drug Discovery, Otsuka Pharmaceutical Co
Liu, Keyue Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kaken ID researchmap
Nishibori, Masahiro Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Tsukita, Sohei Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine
Yamada, Tetsuya Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine
Katagiri, Hideki Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine
Shirakawa, Ryutaro Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University
Horiuchi, Hisanori Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University
Abstract
Metformin is the first-line drug in the treatment of type 2 diabetes. In addition to its hypoglycemic effect, metformin has an anti-inflammatory function, but the precise mechanism promoting this activity remains unclear. High mobility group box 1 (HMGB1) is an alarmin that is released from necrotic cells and induces inflammatory responses by its cytokine-like activity and is, therefore, a target of anti-inflammatory therapies. Here we identified HMGB1 as a novel metformin-binding protein by affinity purification using a biotinylated metformin analogue. Metformin directly bound to the C-terminal acidic tail of HMGB1. Both in vitro and in vivo, metformin inhibited inflammatory responses induced by full-length HMGB1 but not by HMGB1 lacking the acidic tail. In an acetaminophen-induced acute liver injury model in which HMGB1 released from injured cells exacerbates the initial injury, metformin effectively reduced liver injury and had no additional inhibitory effects when the extracellular HMGB1 was blocked by anti-HMGB1-neutralizing antibody. In summary, we report for the first time that metformin suppresses inflammation by inhibiting the extracellular activity of HMGB1. Because HMGB1 plays a major role in inflammation, our results suggest possible new ways to manage HMGB1-induced inflammation.
Keywords
cytokine
inflammation
liver injury
metformin
p38 MAPK
Published Date
2017-05
Publication Title
Journal of Biological Chemistry
Volume
volume292
Issue
issue20
Publisher
American Society for Biochemistry and Molecular Biology
Start Page
8436
End Page
8446
ISSN
0021-9258
NCID
AA00251083
Content Type
Journal Article
language
English
OAI-PMH Set
岡山大学
Copyright Holders
https://creativecommons.org/licenses/by/4.0/deed.ja
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PubMed ID
DOI
Web of Science KeyUT
Related Url
https://doi.org/10.1074/jbc.M116.769380