Journal
FASEB JOURNAL
Volume 32, Issue 7, Pages 3803-3815Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201701187R
Keywords
idiopathic pulmonary fibrosis; metabolism; fibrosis
Categories
Funding
- Public Health Service from the U.S. National Institutes of Health (NIH) National Institute of General Medical Sciences [GM-55816, GM-54200]
- Mayo Brain Specialized Programs of Research Excellence (SPORE) [CA-108961]
- Caerus Foundation [91736058]
- Mayo Foundation
- Public Health Service Grant from the NIH National Cancer Institute [CA-116623]
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Evidence is provided that the fibroproliferative actions of TGF- are dependent on a metabolic adaptation that sustains pathologic growth. Specifically, profibrotic TGF- signaling is shown to require fatty acid synthase (FASN), an essential anabolic enzyme responsible for the de novo synthesis of fatty acids. With the use of pharmacologic and genetic approaches, we show that TGF--stimulated FASN expression is independent of Smad2/3 and is mediated via mammalian target of rapamycin complex 1. In the absence of FASN activity or protein, TGF--driven fibrogenic processes are reduced with no apparent toxicity. Furthermore, as increased FASN expression was also observed to correlate with the degree of lung fibrosis in bleomycin-treated mice, inhibition of FASN was examined in a murine-treatment model of pulmonary fibrosis. Remarkably, inhibition of FASN not only decreased expression of profibrotic targets, but lung function was also stabilized/improved, as assessed by peripheral blood oxygenation.Jung, M.-Y., Kang, J.-H., Hernandez, D. M., Yin, X., Andrianifahanana, M., Wang, Y., Gonzalez-Guerrico, A., Limper, A. H., Lupu, R., Leof, E. B. Fatty acid synthase is required for profibrotic TGF- signaling.
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