美国哈佛医学院Anna Greka课题组发现，FALCON可系统研究游离脂肪酸的生物学特性并鉴定出一种新的脂质毒性介体。这一研究成果于2023年4月18日在线发表在国际学术期刊《细胞—代谢》上。

研究人员报告了FALCON（fatty acid library for comprehensive ontologies）的设计和实施，这是一个针对61种结构不同游离脂肪酸（FFA）的无偏倚、可扩展、多模式检测方法。研究人员确定了一个与膜流动性下降有关的脂毒性单不饱和脂肪酸子集。此外，研究人员优先考虑了反映有害FFA暴露和2型糖尿病（T2D）遗传风险综合影响的基因。研究人员发现，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FFA代谢紊乱有关的各种疾病所急需的靶点。

据介绍，细胞暴露于FFA与肥胖相关疾病的发病机制有关联。然而，目前还没有可扩展的方法来全面评估人类血浆中循环的各种FFA。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。

附：英文原文

Title: FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity

Author: Nicolas Wieder, Juliana Coraor Fried, Choah Kim, Eriene-Heidi Sidhom, Matthew R. Brown, Jamie L. Marshall, Carlos Arevalo, Moran Dvela-Levitt, Maria Kost-Alimova, Jonas Sieber, Katlyn R. Gabriel, Julian Pacheco, Clary Clish, Hamdah Shafqat Abbasi, Shantanu Singh, Justine C. Rutter, Martine Therrien, Haejin Yoon, Zon Weng Lai, Aaron Baublis, Renuka Subramanian, Ranjan Devkota, Jonnell Small, Vedagopuram Sreekanth, Myeonghoon Han, Donghyun Lim, Anne E. Carpenter, Jason Flannick, Hilary Finucane, Marcia C. Haigis, Melina Claussnitzer, Eric Sheu, Beth Stevens, Bridget K. Wagner, Amit Choudhary, Jillian L. Shaw, Juan Lorenzo Pablo, Anna Greka

Issue&Volume: 2023-04-18

Abstract: 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.

DOI: 10.1016/j.cmet.2023.03.018

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00123-7