The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASN^KD) in ECs impedes vessel sprouting by reducing proliferation. Endothelial loss of FASN impaired angiogenesis in vivo, while FASN blockade reduced pathological ocular neovascularization, at >10-fold lower doses than used for anti-cancer treatment. Impaired angiogenesis was not due to energy stress, redox imbalance, or palmitate depletion. Rather, FASN^KD elevated malonyl-CoA levels, causing malonylation (a post-translational modification) of mTOR at lysine 1218 (K1218). mTOR K-1218 malonylation impaired mTOR complex 1 (mTORC1) kinase activity, thereby reducing phosphorylation of downstream targets (p70S6K/4EBP1). Silencing acetyl-CoA carboxylase 1 (an enzyme producing malonyl-CoA) normalized malonyl-CoA levels and reactivated mTOR in FASN^KD ECs. Mutagenesis unveiled the importance of mTOR K1218 malonylation for angiogenesis. This study unveils a novel role of FASN in metabolite signaling that contributes to explaining the anti-angiogenic effect of FASN blockade.

中文翻译：

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脂肪酸合酶抑制血管生成受损涉及mTOR丙二酰化。

脂肪酸合成在内皮细胞（ECs）中的作用仍然不完全被表征。我们报告说，EC中的脂肪酸合酶敲低（FASN ^KD）通过减少增殖来阻止血管发芽。FASN的内皮功能丧失会损害体内血管生成，而FASN的阻断作用会减少病理性眼部新血管形成，其剂量要比抗癌治疗的剂量低10倍以上。血管生成受损不是由于能量紧张，氧化还原失衡或棕榈酸酯消耗引起的。而是FASN ^KD丙二酰辅酶A水平升高，导致赖氨酸1218（K1218）的mTOR发生丙二酰化（翻译后修饰）。mTOR K-1218的丙二酰化作用会削弱mTOR复合物1（mTORC1）激酶的活性，从而降低下游靶标（p70S6K / 4EBP1）的磷酸化。使FASN ^KD EC中的乙酰辅酶A羧化酶1（产生丙二酰辅酶A的酶）沉默，使丙二酰辅酶A水平标准化并重新激活mTOR 。诱变揭示了mTOR K1218丙二酰化对血管生成的重要性。这项研究揭示了FASN在代谢物信号传导中的新作用，有助于解释FASN阻断剂的抗血管生成作用。