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

• Published in: Cell metabolism Vol. 35; no. 5; pp. 887 - 905.e11
• Main Authors: Wieder, Nicolas, Fried, Juliana Coraor, Kim, Choah, Sidhom, Eriene-Heidi, Brown, Matthew R., Marshall, Jamie L., Arevalo, Carlos, Dvela-Levitt, Moran, Kost-Alimova, Maria, Sieber, Jonas, Gabriel, Katlyn R., Pacheco, Julian, Clish, Clary, Abbasi, Hamdah Shafqat, Singh, Shantanu, Rutter, Justine C., Therrien, Martine, Yoon, Haejin, Lai, Zon Weng, Baublis, Aaron, Subramanian, Renuka, Devkota, Ranjan, Small, Jonnell, Sreekanth, Vedagopuram, Han, Myeonghoon, Lim, Donghyun, Carpenter, Anne E., Flannick, Jason, Finucane, Hilary, Haigis, Marcia C., Claussnitzer, Melina, Sheu, Eric, Stevens, Beth, Wagner, Bridget K., Choudhary, Amit, Shaw, Jillian L., Pablo, Juan Lorenzo, Greka, Anna
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.05.2023
• Subjects: Biology; CMIP; Diabetes Mellitus, Type 2; erucic acid; Fatty Acids; Fatty Acids, Nonesterified - metabolism; GWAS; Humans; kidney; lipidomics; microglia; obesity; pancreatic β cell; Signal Transduction; transcriptomics; type 2 diabetes; erucic acid; kidney; pancreatic β cell; type 2 diabetes; GWAS; transcriptomics; microglia; obesity; lipidomics; CMIP
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2023.03.018

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. [Display omitted] •Fatty acid library for comprehensive ontologies (FALCON) profiles diverse fatty acids•FALCON’s unbiased grouping of fatty acids (FFAs) is applicable to multiple cell types•Lipotoxic FFAs include monounsaturated fatty acids that decrease membrane fluidity•FALCON identifies CMIP at the intersection of environmental and genetic disease risk Wieder and Coraor Fried et al. designed fatty acid library for comprehensive ontologies (FALCON) to systematically profile the effects of diverse free fatty acids (FFAs) on different cell types. Unbiased grouping of FFAs revealed a novel subset of toxic monounsaturated FFAs, and integration with human genomic data revealed lipotoxicity regulators.