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

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 BaublisRenuka 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

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish
Pages (from-to)887-905.e11
JournalCell Metabolism
Volume35
Issue number5
DOIs
StatePublished - 2 May 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Funding

We thank Katie Liguori for excellent graphic design work and colleagues in the Center for the Development of Therapeutics for their assistance in the preparation of the FFA library. This work was supported by a seed grant from the Broad Institute of MIT and Harvard (Bn10), DK095045 , DK099465 , and Cure Alzheimer’s Fund (to A.G.) . N.W. was supported by a Deutsche Forschungsgesellschaft Fellowship ( WI 4612/1-1 ) and is a participant in the BIH Digital Clinician Scientist Program funded by the DFG, Charité – Universitätsmedizin Berlin and the Berlin Institute of Health at Charité (BIH) . J.C.F. and J.C.R. were supported by the National Institute of General Medical Sciences ( T32GM007753 to both and T32GM007726 to J.C.F.). E.-H.S., C.K., and M.R.B. were supported by the National Institutes of Health ( F30DK112477 , F31DK126252 , and K00DK123834 , respectively). M.D.-L. was supported by a Broad-Israeli Science Foundation Fellowship . E.S. was supported by NIH 1-R01-DK126855-01 and an American Surgical Association Foundation Fellowship. M.C. was supported by FNIH AMP-T2D RFB8b and NIDDK UM1 DK126185 . A.E.C. and S.S. were supported by the National Institutes of Health (NIH MIRA R35 GM122547 ). R.D. was supported by the Knut and Alice Wallenberg Foundation, Sweden (KAW 2019.0580 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Katie Liguori for excellent graphic design work and colleagues in the Center for the Development of Therapeutics for their assistance in the preparation of the FFA library. This work was supported by a seed grant from the Broad Institute of MIT and Harvard (Bn10), DK095045, DK099465, and Cure Alzheimer's Fund (to A.G.). N.W. was supported by a Deutsche Forschungsgesellschaft Fellowship (WI 4612/1-1) and is a participant in the BIH Digital Clinician Scientist Program funded by the DFG, Charité – Universitätsmedizin Berlin and the Berlin Institute of Health at Charité (BIH). J.C.F. and J.C.R. were supported by the National Institute of General Medical Sciences (T32GM007753 to both and T32GM007726 to J.C.F.). E.-H.S. C.K. and M.R.B. were supported by the National Institutes of Health (F30DK112477, F31DK126252, and K00DK123834, respectively). M.D.-L. was supported by a Broad-Israeli Science Foundation Fellowship. E.S. was supported by NIH 1-R01-DK126855-01 and an American Surgical Association Foundation Fellowship. M.C. was supported by FNIH AMP-T2D RFB8b and NIDDK UM1 DK126185. A.E.C. and S.S. were supported by the National Institutes of Health (NIH MIRA R35 GM122547). R.D. was supported by the Knut and Alice Wallenberg Foundation, Sweden (KAW 2019.0580). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. N.W. J.C.F. J.L.P. and A.G. conceived the study and designed the experiments. N.W. and J.C.F. conducted experiments and analyzed the data; experimental work was contributed by C.K. E.-H.S. J.L.M. M.D.-L. J. Sieber, J.P. J.L.P. J.C.R. M.T. H.Y. Z.W.L. A.B. R.D. J. Small, V.S. M.H. and D.L.; data analysis was contributed by C.K. E.-H.S. M.R.B. C.A. M.K.-A. K.R.G. C.C. H.S.A. S.S. R.S. A.C. J.F. and J.L.P. N.W. J.C.F. J.L.P. J.L.S. and A.G. wrote the manuscript; A.G. directed the study. All authors read the manuscript and approved its contents. N.W. J.C.F. and A.G. are co-inventors of a patent on the composition, method, and use for FFA screening, application no: 52199-550P01US. A.G. serves as a founding advisor to a new company launched by Atlas Ventures, an agreement reviewed and managed by Brigham and Women's Hospital, Mass General Brigham, and the Broad Institute of MIT and Harvard in accordance with their conflict of interest policies. We support inclusive, diverse, and equitable conduct of research.

FundersFunder number
Atlas Ventures
Berlin Institute of Health at Charité
Broad–Israeli Science Foundation
FNIH AMP-T2D RFB8b
National Institutes of Health1-R01-DK126855-01, F30DK112477, K00DK123834, F31DK126252
National Institute of General Medical SciencesT32GM007753, T32GM007726
National Institute of Diabetes and Digestive and Kidney DiseasesMIRA R35 GM122547, UM1 DK126185
California Department of Fish and Game
American Surgical Association Foundation
Harvard UniversityDK099465, Bn10, DK095045
Cure Alzheimer's FundWI 4612/1-1
Broad Institute
Charité – Universitätsmedizin Berlin
Knut och Alice Wallenbergs StiftelseKAW 2019.0580

    Keywords

    • CMIP
    • GWAS
    • erucic acid
    • kidney
    • lipidomics
    • microglia
    • obesity
    • pancreatic β cell
    • transcriptomics
    • type 2 diabetes

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