FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity
Author:
Wieder Nicolas, Fried Juliana CoraorORCID, Kim ChoahORCID, Sidhom Eriene-HeidiORCID, Brown Matthew R., Marshall Jamie L.ORCID, Arevalo CarlosORCID, Dvela-Levitt MoranORCID, Kost-Alimova Maria, Sieber JonasORCID, Gabriel Katlyn R., Pacheco Julian, Clish ClaryORCID, Abbasi Hamdah Shafqat, Singh Shantanu, Rutter Justine, Therrien MartineORCID, Yoon HaejinORCID, Lai Zon WengORCID, Baublis Aaron, Subramanian Renuka, Devkota Ranjan, Small JonnellORCID, Sreekanth Vedagopuram, Han Myeonghoon, Lim DonghyunORCID, Carpenter Anne E., Flannick Jason, Finucane Hilary, Haigis Marcia C., Claussnitzer MelinaORCID, Sheu Eric, Stevens Beth, Wagner Bridget K., Choudhary Amit, Shaw Jillian L.ORCID, Pablo Juan Lorenzo, Greka AnnaORCID
Abstract
SummaryCellular exposure to free fatty acids (FFA) is implicated in the pathogenesis of obesity-associated diseases. However, studies to date have assumed that a few select FFAs are representative of broad structural categories, and there are no scalable approaches to comprehensively assess the biological processes induced by exposure to diverse FFAs circulating in human plasma. Furthermore, assessing how these FFA- mediated processes interact with genetic risk for disease remains elusive. Here we report the design and implementation of FALCON (Fatty Acid Library for Comprehensive ONtologies) as an unbiased, scalable and multimodal interrogation of 61 structurally diverse FFAs. We identified a subset of lipotoxic monounsaturated fatty acids (MUFAs) with a distinct lipidomic profile associated with decreased membrane fluidity. Furthermore, we developed a new approach to prioritize genes that reflect the combined effects of exposure to harmful FFAs and genetic risk for type 2 diabetes (T2D). Importantly, we found that c-MAF inducing protein (CMIP) protects cells from exposure to FFAs by modulating Akt signaling and we validated the role of CMIP in human pancreatic beta cells. 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.HighlightsFALCON (Fatty Acid Library for Comprehensive ONtologies) enables multimodal profiling of 61 free fatty acids (FFAs) to reveal 5 FFA clusters with distinct biological effectsFALCON is applicable to many and diverse cell typesA subset of monounsaturated FAs (MUFAs) equally or more toxic than canonical lipotoxic saturated FAs (SFAs) leads to decreased membrane fluidityNew approach prioritizes genes that represent the combined effects of environmental (FFA) exposure and genetic risk for diseaseC-Maf inducing protein (CMIP) is identified as a suppressor of FFA-induced lipotoxicity via Akt-mediated signaling
Publisher
Cold Spring Harbor Laboratory
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