TY - JOUR
T1 - Fatty acid synthase is required for profibrotic TGF-b signaling
AU - Jung, Mi Yeon
AU - Kang, Jeong Han
AU - Hernandez, Danielle M.
AU - Yin, Xueqian
AU - Andrianifahanana, Mahefatiana
AU - Wang, Youli
AU - Gonzalez-Guerrico, Anatilde
AU - Limper, Andrew H.
AU - Lupu, Ruth
AU - Leof, Edward B.
N1 - Publisher Copyright:
© FASEB
PY - 2018/7
Y1 - 2018/7
N2 - Evidence is provided that the fibroproliferative actions of TGF-b are dependent on a metabolic adaptation that sustains pathologic growth. Specifically, profibrotic TGF-b 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-b-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-b-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-b signaling. FASEB J. 32, 3803–3815 (2018). www.fasebj.org
AB - Evidence is provided that the fibroproliferative actions of TGF-b are dependent on a metabolic adaptation that sustains pathologic growth. Specifically, profibrotic TGF-b 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-b-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-b-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-b signaling. FASEB J. 32, 3803–3815 (2018). www.fasebj.org
KW - Fibrosis
KW - Idiopathic pulmonary fibrosis
KW - Metabolism
UR - http://www.scopus.com/inward/record.url?scp=85049302032&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049302032&partnerID=8YFLogxK
U2 - 10.1096/fj.201701187R
DO - 10.1096/fj.201701187R
M3 - Article
C2 - 29475397
AN - SCOPUS:85049302032
SN - 0892-6638
VL - 32
SP - 3803
EP - 3815
JO - FASEB Journal
JF - FASEB Journal
IS - 7
ER -