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.
Highlights
Macrophages display functional plasticity [1]
We show that proinflammatory macrophages are characterized by increased endogenous fatty acid synthesis and the inhibition of fatty acid synthase (FASN) downregulates proinflammatory responses of macrophages
De novo fatty acid synthesis is regulated by three key lipogenic enzymes, FASN, acetyl-CoA carboxylase (ACACA), and ATP citrate lyase (ACLY) [32], so we firstly detected their protein levels to analyze whether LPS stimulus influenced fatty acid synthesis in macrophages
Summary
Macrophages display functional plasticity [1]. In recent years, researchers have been recognizing that activation, differentiation, and polarization of macrophages can trigger distinct changes in intracellular metabolic pathways (metabolic reprograming), which in turn contribute to shaping the immune responses and immune cell fate [2, 3]. Several studies have revealed that proinflammatory stimuli upregulate de novo fatty acid synthesis in macrophages [6]. Though a number of studies have indicated that exogenous fatty acid activates TLR related inflammatory signaling pathway in immune cells [7, 8], the endogenous fatty acid has been being evidenced to regulate inflammation and immune as well [9, 10]. Palmitoylation could enhance the hydrophobicity of protein and further influence protein trafficking and functions, which bridges fatty acid metabolism and other cellular activities including inflammatory responses. Warburg effect as a cancer target [16], we inferred that fatty acid synthesis was a novel target pathway to suppress proinflammatory activation of macrophages
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