An unexpected link between fatty acid synthase and cholesterol synthesis in proinflammatory macrophage activation.
An unexpected link between fatty acid synthase and cholesterol synthesis in proinflammatory macrophage activation.
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DOI：
10.1074/jbc.ra118.001921
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发表时间：
2018-04-13
期刊：
影响因子：
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通讯作者：
O'Neill LA
中科院分区：
文献类型：
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作者：
Carroll RG;Zasłona Z;Galván-Peña S;Koppe EL;Sévin DC;Angiari S;Triantafilou M;Triantafilou K;Modis LK;O'Neill LA
不同的免疫激活状态需要不同的免疫细胞代谢特征和活动。例如，抑制催化长链脂肪酸合成的脂肪酸合成酶（FASN）可以阻止巨噬细胞的促炎反应；然而，这种酶在这种反应中的确切作用仍然不清楚。与之前的研究一致，我们发现FASN对于脂多糖诱导的toll样受体（TLR）介导的巨噬细胞激活至关重要。有趣的是，只有阻断乙酰辅酶a合成上游FASN的药物，包括表征良好的FASN抑制剂C75，才能抑制TLR4信号传导，而作用于下游的药物则没有作用。我们发现乙酰辅酶a可以克服C75的抑制作用，而其他FASN代谢物，包括棕榈酸酯，不能阻止C75介导的抑制作用。这表明乙酰乙酰辅酶a在炎症中的作用是意想不到的，独立于它在棕榈酸盐合成中的作用。我们的证据进一步表明，由FASN活性产生的乙酰乙酰辅酶a促进胆固醇的产生，这表明脂肪酸合成和胆固醇合成之间存在令人惊讶的联系。我们进一步证明，这一过程是TLR4进入脂筏和促进TLR4信号传导所必需的。总之，我们发现了FASN和胆固醇合成之间意想不到的联系，这似乎是TLR信号转导和促炎巨噬细胞激活所必需的。
Different immune activation states require distinct metabolic features and activities in immune cells. For instance, inhibition of fatty acid synthase (FASN), which catalyzes the synthesis of long-chain fatty acids, prevents the proinflammatory response in macrophages; however, the precise role of this enzyme in this response remains poorly defined. Consistent with previous studies, we found here that FASN is essential for lipopolysaccharide-induced, Toll-like receptor (TLR)-mediated macrophage activation. Interestingly, only agents that block FASN upstream of acetoacetyl-CoA synthesis, including the well-characterized FASN inhibitor C75, inhibited TLR4 signaling, while those acting downstream had no effect. We found that acetoacetyl-CoA could overcome C75's inhibitory effect, whereas other FASN metabolites, including palmitate, did not prevent C75-mediated inhibition. This suggested an unexpected role for acetoacetyl-CoA in inflammation that is independent of its role in palmitate synthesis. Our evidence further suggested that acetoacetyl-CoA arising from FASN activity promotes cholesterol production, indicating a surprising link between fatty acid synthesis and cholesterol synthesis. We further demonstrate that this process is required for TLR4 to enter lipid rafts and facilitate TLR4 signaling. In conclusion, we have uncovered an unexpected link between FASN and cholesterol synthesis that appears to be required for TLR signal transduction and proinflammatory macrophage activation.