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Nat Commun. 2017 Jul 12;8:16040. doi: 10.1038/ncomms16040.

BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases.

Author information

1
Ergon Pharmaceuticals, LLC, P.O. Box 1001, Silver Spring, Maryland 20910, USA.
2
Centre for Complement and Inflammation Research, Imperial College London, London W12 0NN, UK.
3
Division of Brain Sciences, Imperial College Faculty of Medicine, London W12 0NN, UK.
4
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
5
Institute Pasteur, Fondazione Cenci Bolognetti, Rome 00161, Italy.
6
Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, London W12 0NN, UK.
7
Biochemistry and Nutrition, Des Moines University, Des Moines, Iowa 50312, USA.

Abstract

Branched-chain aminotransferases (BCAT) are enzymes that initiate the catabolism of branched-chain amino acids (BCAA), such as leucine, thereby providing macromolecule precursors; however, the function of BCATs in macrophages is unknown. Here we show that BCAT1 is the predominant BCAT isoform in human primary macrophages. We identify ERG240 as a leucine analogue that blocks BCAT1 activity. Selective inhibition of BCAT1 activity results in decreased oxygen consumption and glycolysis. This decrease is associated with reduced IRG1 levels and itaconate synthesis, suggesting involvement of BCAA catabolism through the IRG1/itaconate axis within the tricarboxylic acid cycle in activated macrophages. ERG240 suppresses production of IRG1 and itaconate in mice and contributes to a less proinflammatory transcriptome signature. Oral administration of ERG240 reduces the severity of collagen-induced arthritis in mice and crescentic glomerulonephritis in rats, in part by decreasing macrophage infiltration. These results establish a regulatory role for BCAT1 in macrophage function with therapeutic implications for inflammatory conditions.

PMID:
28699638
PMCID:
PMC5510229
DOI:
10.1038/ncomms16040
[Indexed for MEDLINE]
Free PMC Article

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