Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity

Takahiro Horiuchi, Natsumi Sakata, Yoshihiro Narumi, Tomohiro Kimura, Takashi Hayashi, Keisuke Nagano, Keyue Liu, Masahiro Nishibori, Sohei Tsukita, Tetsuya Yamada, Hideki Katagiri, Ryutaro Shirakawa, Hisanori Horiuchi

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)8436-8446
Number of pages11
JournalJournal of Biological Chemistry
Volume292
Issue number20
DOIs
Publication statusPublished - May 19 2017

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Metformin
Inflammation
Liver
Wounds and Injuries
Anti-Inflammatory Agents
Alarmins
Acetaminophen
Medical problems
Neutralizing Antibodies
Hypoglycemic Agents
Type 2 Diabetes Mellitus
Purification
Carrier Proteins
Cytokines
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Horiuchi, T., Sakata, N., Narumi, Y., Kimura, T., Hayashi, T., Nagano, K., ... Horiuchi, H. (2017). Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity. Journal of Biological Chemistry, 292(20), 8436-8446. https://doi.org/10.1074/jbc.M116.769380

Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity. / 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.

In: Journal of Biological Chemistry, Vol. 292, No. 20, 19.05.2017, p. 8436-8446.

Research output: Contribution to journalArticle

Horiuchi, T, Sakata, N, Narumi, Y, Kimura, T, Hayashi, T, Nagano, K, Liu, K, Nishibori, M, Tsukita, S, Yamada, T, Katagiri, H, Shirakawa, R & Horiuchi, H 2017, 'Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity', Journal of Biological Chemistry, vol. 292, no. 20, pp. 8436-8446. https://doi.org/10.1074/jbc.M116.769380
Horiuchi T, Sakata N, Narumi Y, Kimura T, Hayashi T, Nagano K et al. Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity. Journal of Biological Chemistry. 2017 May 19;292(20):8436-8446. https://doi.org/10.1074/jbc.M116.769380
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. / Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 20. pp. 8436-8446.
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