Fueling fibrosis: BCAT1 links branched-chain amino acid metabolism to collagen production
Marco Ronfini, John W. Elrod
Marco Ronfini, John W. Elrod
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Commentary

Fueling fibrosis: BCAT1 links branched-chain amino acid metabolism to collagen production

Abstract

Fibrosis remains a major driver of organ dysfunction, yet the metabolic programs that sustain extracellular matrix production are incompletely understood. In this issue of the JCI, Takizawa and colleagues identified branched-chain amino acid transaminase 1 (BCAT1) as a crucial metabolic regulator of fibroblast activation and fibrosis in a model of cardiac fibrosis. Their observations were corroborated by analyses of datasets from patients with heart failure with preserved ejection fraction and metabolic dysfunction–associated steatohepatitis. They report that by coupling mechanical and TGF-β signaling to a proline biosynthesis and utilization program, BCAT1 enhanced collagen production in activated cardiac fibroblasts. These findings place branched-chain amino acid metabolism as a pivotal contributor to fibroblast activation and highlight BCAT1 as a promising therapeutic target for fibrotic disease.

Authors

Marco Ronfini, John W. Elrod

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Figure 1

BCAT1 links BCAA metabolism to collagen production.

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BCAT1 links BCAA metabolism to collagen production. Takizawa et al. (9) ...
Takizawa et al. (9) identified BCAT1 as a crucial metabolic regulator of fibroblast activation and fibrosis. Their findings support a mechanism by which (i) mechanical stress and TGF-β signaling induce BCAT1 expression in protomyofibroblasts. (ii) Subsequently, BCAT1-mediated BCAA metabolism potentially promotes phosphorylation of HDAC5 and activation of SMAD3, leading to increased transcription of ALDH18A1, PYCR1, and EPRS. (iii) These genes encode enzymes that enhance proline synthesis and utilization, supporting efficient production of collagens I and III and ECM deposition. Genetic or pharmacologic inhibition of BCAT1 disrupted this pathway, reducing fibrosis and improving cardiac function after MI.