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4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to exert anti-inflammatory effects.
- Source :
-
Nature communications [Nat Commun] 2019 Nov 08; Vol. 10 (1), pp. 5091. Date of Electronic Publication: 2019 Nov 08. - Publication Year :
- 2019
-
Abstract
- Activated macrophages switch from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect, presenting a potential therapeutic target in inflammatory disease. The endogenous metabolite itaconate has been reported to regulate macrophage function, but its precise mechanism is not clear. Here, we show that 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) directly alkylates cysteine residue 22 on the glycolytic enzyme GAPDH and decreases its enzyme activity. Glycolytic flux analysis by U <superscript>13</superscript> C glucose tracing provides evidence that 4-OI blocks glycolytic flux at GAPDH. 4-OI thereby downregulates aerobic glycolysis in activated macrophages, which is required for its anti-inflammatory effects. The anti-inflammatory effects of 4-OI are replicated by heptelidic acid, 2-DG and reversed by increasing wild-type (but not C22A mutant) GAPDH expression. 4-OI protects against lipopolysaccharide-induced lethality in vivo and inhibits cytokine release. These findings show that 4-OI has anti-inflammatory effects by targeting GAPDH to decrease aerobic glycolysis in macrophages.
- Subjects :
- Alkylation
Animals
Antimetabolites pharmacology
Cysteine drug effects
Cysteine genetics
Cysteine metabolism
Deoxyglucose pharmacology
Down-Regulation
Endotoxemia immunology
Glucose metabolism
Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) antagonists & inhibitors
Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) metabolism
Inflammation immunology
Interleukin-1beta drug effects
Interleukin-1beta immunology
Lipopolysaccharides pharmacology
Macrophage Activation immunology
Macrophages immunology
Macrophages metabolism
Mice
Nitric Oxide Synthase Type II drug effects
Nitric Oxide Synthase Type II immunology
Oxidative Phosphorylation drug effects
RAW 264.7 Cells
Sesquiterpenes pharmacology
Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) drug effects
Glycolysis drug effects
Macrophages drug effects
Succinates pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 31704924
- Full Text :
- https://doi.org/10.1038/s41467-019-13078-5