FullText URL J. Biol. Chem_292_20_8436.pdf
Author Horiuchi, Takahiro| Sakata, Natsumi| Narumi, Yoshihiro| Kimura, Tomohiro| Hayashi, Takashi| Nagano, Keisuke| Liu, Keyue| Nishibori, Masahiro| Tsukita, Sohei| Yamada, Tetsuya| Katagiri, Hideki| Shirakawa, Ryutaro| Horiuchi, Hisanori|
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 英語
OAI-PMH Set 岡山大学
Copyright Holders https://creativecommons.org/licenses/by/4.0/deed.ja
File Version publisher
PubMed ID 28373282
DOI 10.1074/jbc.M116.769380
Web of Sience KeyUT 000401788600027
Related Url https://doi.org/10.1074/jbc.M116.769380