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

Autor:	Wieder N; 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., Fried JC; 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., Kim C; 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., Sidhom EH; 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., Brown MR; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Marshall JL; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Arevalo C; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Dvela-Levitt M; 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; The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel., Kost-Alimova M; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Sieber J; Department of Endocrinology, Metabolism and Cardiovascular Systems, University of Fribourg, Fribourg, Switzerland., Gabriel KR; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Pacheco J; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Clish C; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Abbasi HS; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Singh S; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Rutter JC; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA., Therrien M; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Yoon H; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center for Cancer Research at Harvard, Boston, MA 02115, USA., Lai ZW; Harvard Chan Advanced Multiomics Platform, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA., Baublis A; Harvard Chan Advanced Multiomics Platform, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA., Subramanian R; Laboratory for Surgical and Metabolic Research, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Devkota R; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Small J; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA; Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Sreekanth V; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Divisions of Renal Medicine and Engineering, Brigham and Women's Hospital, Boston, MA 02115, USA., Han M; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Lim D; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Carpenter AE; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Flannick J; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA., Finucane H; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Mass General Hospital, Boston, MA 02114, USA., Haigis MC; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center for Cancer Research at Harvard, Boston, MA 02115, USA., Claussnitzer M; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA; Metabolism Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Sheu E; Laboratory for Surgical and Metabolic Research, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA., Stevens B; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA; Boston Children's Hospital, F.M. Kirby Neurobiology Center, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA., Wagner BK; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Choudhary A; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA; Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Divisions of Renal Medicine and Engineering, Brigham and Women's Hospital, Boston, MA 02115, USA., Shaw JL; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Pablo JL; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Greka A; 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. Electronic address: agreka@bwh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2023 May 02; Vol. 35 (5), pp. 887-905.e11. Date of Electronic Publication: 2023 Apr 18.
DOI:	10.1016/j.cmet.2023.03.018
Abstrakt:	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. Competing Interests: Declaration of interests 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. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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