Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity.
Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity.
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DOI：
10.1074/jbc.m116.769380
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发表时间：
2017-05-19
期刊：
影响因子：
--
通讯作者：
Horiuchi H
中科院分区：
文献类型：
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作者：
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
二甲双胍是治疗2型糖尿病的一线药物。除了降血糖作用外，二甲双胍还具有抗炎作用，但促进这种活性的确切机制仍不清楚。高迁移率族蛋白1（HMGB 1）是一种由坏死细胞释放的警报素，通过其类胡萝卜素活性诱导炎症反应，因此是抗炎治疗的靶点。在这里，我们确定HMGB 1作为一种新的二甲双胍结合蛋白的亲和纯化使用生物素化二甲双胍类似物。甲硫氨酸直接与HMGB 1的C-末端酸性尾结合。在体外和体内，二甲双胍抑制全长HMGB 1诱导的炎症反应，但不抑制缺乏酸性尾的HMGB 1诱导的炎症反应。在对乙酰氨基酚诱导的急性肝损伤模型中，损伤细胞释放的HMGB 1加重了初始损伤，二甲双胍有效地减轻了肝损伤，并且当细胞外HMGB 1被抗HMGB 1中和抗体阻断时，没有额外的抑制作用。总之，我们首次报道二甲双胍通过抑制HMGB 1的细胞外活性来抑制炎症。由于HMGB 1在炎症中起着重要作用，我们的研究结果提出了可能的新方法来管理HMGB 1诱导的炎症。
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.