title: Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity.
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. Bothin vitroandin 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.
authors.affiliation: Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Horiuchi
authors.affiliation: Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Sakata
authors.affiliation: Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Narumi
authors.affiliation: Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Biomedical Technology Research Center, Tokushima Research Institute.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: First Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nagano
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Keyue
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Sohei
authors.initials: S
authors.lastname: Tsukita
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
authors.affiliation: Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Electronic address: ryutaro.shirakawa.b1@tohoku.ac.jp.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Shirakawa
authors.affiliation: Department of Molecular and Cellular Biology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. Electronic address: hisanori.horiuchi.e8@tohoku.ac.jp.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Horiuchi
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000494:pharmacology; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008687:Metformin / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D011485:Protein Binding; D000072417:Protein Domains; D000067996:RAW 264.7 Cells
chemical_list: D057134:Antibodies, Neutralizing; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; C582808:HMGB1 protein, mouse; D008687:Metformin
keywords: cytokine; inflammation; liver injury; metformin; p38 MAPK