Cell Death and Disease (Oct 2021)

Metformin alleviates inflammation through suppressing FASN-dependent palmitoylation of Akt

  • Wenfang Xiong,
  • Kuo-Yang Sun,
  • Yan Zhu,
  • Xiaoqi Zhang,
  • Yi-Hua Zhou,
  • Xiaoping Zou

DOI
https://doi.org/10.1038/s41419-021-04235-0
Journal volume & issue
Vol. 12, no. 10
pp. 1 – 15

Abstract

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Abstract Metformin, traditionally regarded as a hypoglycemic drug, has been studied in other various fields including inflammation. The specific mechanism of metformin’s effect on immune cells remains unclear. Herein, it is verified that LPS-induced macrophages are characterized by enhanced endogenous fatty acid synthesis and the inhibition of fatty acid synthase (FASN) downregulates proinflammatory responses. We further show that metformin could suppress such elevation of FASN as well as proinflammatory activation in macrophages. In vivo, metformin treatment ameliorates dextran sulfate sodium (DSS)-induced colitis through impairing proinflammatory activation of colonic lamina propria mononuclear cells (LPMCs). The reduction of FASN by metformin hinders Akt palmitoylation, which further disturbs Akt membrane attachment and its phosphorylation. Metformin-mediated suppression of FASN/Akt pathway and its downstream MAPK signaling contributes to its anti-inflammatory role in macrophages. From the perspective of immunometabolism, our work points towards metformin utilization as an effective and potential intervention against macrophages-involved inflammatory diseases.