Horiuchi Lab. Devertment of molecular and cellular biology, Institute of develoment, aging, and cancer, Tohoku university

Identification of HMGB1 as a novel target of metformin

"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 pro- moting 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 inflam- matory responses induced by full-length HMGB1 but not by HMGB1 lacking the acidic tail. In an acetaminophen-induced acute liver injury model in whichHMGB1 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 ofHMGB1. BecauseHMGB1 plays a major role in inflammation, our results suggest possible new ways to manage HMGB1-induced inflammation." (Horiuchi and Sakata et al, J Biol Chem, 2017)