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

• Published in: Nature communications Vol. 8; no. 1; p. 16040
• Main Authors: Papathanassiu, Adonia E., Ko, Jeong-Hun, Imprialou, Martha, Bagnati, Marta, Srivastava, Prashant K., Vu, Hong A., Cucchi, Danilo, McAdoo, Stephen P., Ananieva, Elitsa A., Mauro, Claudio, Behmoaras, Jacques
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-07-2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/89; 14; 38; 38/77; 42/109; 631/250/2504/342; 64; 692/699/249/1313/498; 82; 82/51; 82/58; 82/80; 96/1; Amino acids; Animals; Arthritis; Arthritis, Experimental - drug therapy; Arthritis, Rheumatoid - drug therapy; Catabolism; Chain branching; Chains; Citric Acid Cycle; Collagen; Drug Evaluation, Preclinical; Enzymes; Gene expression; Glomerulonephritis; Glomerulonephritis - drug therapy; Glycolysis; Humanities and Social Sciences; Humans; Hydro-Lyases - metabolism; Infiltration; Inflammatory diseases; Leucine; Leucine - analogs & derivatives; Leucine - pharmacology; Macrophages; Macrophages, Peritoneal - drug effects; Macrophages, Peritoneal - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; multidisciplinary; Oral administration; Oxygen consumption; Rats; Rodents; Science; Science (multidisciplinary); Succinates - metabolism; Transaminases - antagonists & inhibitors; Transaminases - metabolism; Tricarboxylic acid cycle
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms16040

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.
BCATs catabolize leucine and other BCAAs. Here the authors show that BCAA metabolism affects the broken Krebs cycle, reprogramming macrophages to be less proinflammatory, and show that BCAT1 inhibitor ERG240 can treat arthritis in mice and glomerulonephritis in rats.