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

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Title: BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases
Author(s): Papathanassiu, AE
Ko, JH
Imprialou, M
Bagnati, M
Srivastava, PK
Vu, HA
Cucchi, D
McAdoo, SP
Ananieva, EA
Mauro, C
Behmoaras, JV
Item Type: Journal Article
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.
Publication Date: 12-Jul-2017
Date of Acceptance: 24-May-2017
URI: http://hdl.handle.net/10044/1/48704
DOI: https://dx.doi.org/10.1038/ncomms16040
ISSN: 2041-1723
Publisher: Nature Publishing Group: Nature Communications
Journal / Book Title: Nature Communications
Volume: 8
Sponsor/Funder: Kidney Research UK
Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: RP9/2013
MR/M004716/1
MR/N01121X/1
Copyright Statement: © The Author(s) 2017. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
BRANCHED-CHAIN AMINOTRANSFERASE
EXPERIMENTAL GLOMERULONEPHRITIS
SUCCINATE-DEHYDROGENASE
ALTERNATIVE ACTIVATION
GLUCOSE-METABOLISM
DENDRITIC CELL
POLARIZATION
EXPRESSION
ITACONATE
GENE-1
MD Multidisciplinary
Publication Status: Published
Article Number: 16040
Appears in Collections:Department of Medicine
Faculty of Medicine



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