Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Neurology with Experimental Neurology and Berlin Institute of Health, Charité, 10117 Berlin, Germany.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
Cell Metab. 2023 May 2;35(5):887-905.e11. doi: 10.1016/j.cmet.2023.03.018. Epub 2023 Apr 18.
Cellular exposure to free fatty acids (FFAs) is implicated in the pathogenesis of obesity-associated diseases. However, there are no scalable approaches to comprehensively assess the diverse FFAs circulating in human plasma. Furthermore, assessing how FFA-mediated processes interact with genetic risk for disease remains elusive. Here, we report the design and implementation of fatty acid library for comprehensive ontologies (FALCON), an unbiased, scalable, and multimodal interrogation of 61 structurally diverse FFAs. We identified a subset of lipotoxic monounsaturated fatty acids associated with decreased membrane fluidity. Furthermore, we prioritized genes that reflect the combined effects of harmful FFA exposure and genetic risk for type 2 diabetes (T2D). We found that c-MAF-inducing protein (CMIP) protects cells from FFA exposure by modulating Akt signaling. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism.
细胞暴露于游离脂肪酸（FFAs）与肥胖相关疾病的发病机制有关。然而，目前还没有可扩展的方法来全面评估人血浆中循环的各种游离脂肪酸。此外，评估FFA 介导的过程如何与疾病的遗传风险相互作用仍然难以捉摸。在这里，我们报告了脂肪酸文库的设计和实现，用于全面本体论（FALCON），这是对 61 种结构不同的 FFAs 的无偏、可扩展和多模式询问。我们确定了一组与膜流动性降低相关的脂毒性单不饱和脂肪酸。此外，我们确定了反映有害 FFA 暴露和 2 型糖尿病（T2D）遗传风险综合影响的基因。我们发现，c-MAF 诱导蛋白（CMIP）通过调节 Akt 信号来保护细胞免受 FFA 暴露。总之，FALCON 增强了对基本 FFA 生物学的研究，并提供了一种综合方法来确定与紊乱的 FFA 代谢相关的各种疾病急需的靶标。
