Metformin alleviates inflammation through suppressing FASN-dependent palmitoylation of Akt

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.

Tissue-Specific Downregulation of Fatty Acid Synthase Suppresses Intestinal Adenoma Formation via Coordinated Reprograming of Transcriptome and Metabolism in the Mouse Model of Apc-Driven Colorectal Cancer

“…The components of the tumor microenvironment and the intestinal microbiota can also alter the levels of lipid and metabolites [ 47 ]. FASN is highly expressed in endothelial cells [ 48 , 49 ], immune cells [ 50 , 51 ], and fibroblasts [ 52 ] associated with cancer, suggesting the potential impact of FASN expression in these cells on the levels of FAs observed during adenoma formation. To better understand the effect of FASN on lipid synthesis and lipid uptake and utilization, we plan to perform stable-isotope tracing studies to identify lipid species that drive Apc/FASN-driven carcinogenesis in a better-controlled environment such as organoid culture and primary CRC cell lines.…”

Fatty Acid Synthase inhibitor TVB-3166 prevents S-acylation of the Spike protein of human coronaviruses

“…The growing body of literature has demonstrated FASN, and not exogenous fatty acids, is the primary source of acyl chains for S-acylation (40,46,(53)(54)(55)(56). Using an alternative approach, Zeng et al replaced all ten Cys with Alanine residues and subsequently re-introduced individual Cys residues within the tail and examined the S-acylation using the acyl-biotin exchange.…”

FASN inhibitor TVB-3166 prevents S-acylation of the spike protein of human coronaviruses

“…However, these studies rely on the uptake of fatty acids from the medium. The growing body of literature has demonstrated FASN, and not exogenous fatty acids, is the primary source of acyl chains for S-acylation ( 25 , 54 , 60 , 61 , 62 , 63 ). Using an alternative approach, Zeng et al replaced all ten Cys with Alanine residues and subsequently re-introduced individual Cys residues within the tail and examined the S-acylation using the acyl-biotin exchange.…”

“…However, these studies rely on the uptake of fatty acids from the medium. The growing body of literature has demonstrated FASN, and not exogenous fatty acids, is the primary source of acyl chains for S-acylation (25,54,(60)(61)(62)(63).…”