Fatty acid synthase is required for profibrotic TGF- signaling
Fatty acid synthase is required for profibrotic TGF- signaling
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DOI：
10.1096/fj.201701187r
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发表时间：
2018-07-01
期刊：
影响因子：
4.8
通讯作者：
Leof, Edward B.
中科院分区：
文献类型：
--
作者：
Jung, Mi-Yeon;Kang, Jeong-Han;Leof, Edward B.
有证据表明，TGF-β的纤维增生作用依赖于维持病理生长的代谢适应。具体地，促纤维化TGF-信号传导显示需要脂肪酸合酶（FATCH），一种负责脂肪酸从头合成的必需合成代谢酶。随着药理学和遗传学方法的使用，我们表明，TGF-β刺激的FRESINS的表达是独立的Smad 2/3和介导的哺乳动物雷帕霉素复合物1的目标。在缺乏FGFAP活性或蛋白质的情况下，TGF-β驱动的纤维化过程减少，没有明显的毒性。此外，由于在博来霉素处理的小鼠中还观察到增加的Festival表达与肺纤维化的程度相关，因此在肺纤维化的鼠处理模型中检查Festival的抑制。值得注意的是，如通过外周血液氧合评估的，抑制FGFAP不仅降低了促纤维化靶标的表达，而且肺功能也稳定/改善。是的，康，J. - H、埃尔南德斯，D. M.，Yin，X.，Andrianifahanana，M.，王玉，Gonzalez-Guerrico，A.，Limper，A. H、卢普河，Leof，E. B。脂肪酸合酶是促纤维化TGF-信号传导所必需的。
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.