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FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity.
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; 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.
Afiliação
  • Wieder N; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Fried JC; Department of Medicine, Brigham and Women's Hospital, Boston USA.
  • Kim C; Harvard Medical School, Boston, USA.
  • Sidhom EH; Department of Neurology with Experimental Neurology, Charité, Berlin, Germany.
  • Brown MR; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Marshall JL; Department of Medicine, Brigham and Women's Hospital, Boston USA.
  • Arevalo C; Harvard Medical School, Boston, USA.
  • Dvela-Levitt M; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Kost-Alimova M; Department of Medicine, Brigham and Women's Hospital, Boston USA.
  • Sieber J; Harvard Medical School, Boston, USA.
  • Gabriel KR; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Pacheco J; Department of Medicine, Brigham and Women's Hospital, Boston USA.
  • Clish C; Harvard Medical School, Boston, USA.
  • Abbasi HS; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Singh S; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Rutter J; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Therrien M; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Yoon H; Department of Medicine, Brigham and Women's Hospital, Boston USA.
  • Lai ZW; Harvard Medical School, Boston, USA.
  • Baublis A; The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.
  • Subramanian R; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Devkota R; Department of Endocrinology, Metabolism and Cardiovascular Systems, University of Fribourg, Fribourg, Switzerland.
  • Small J; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Sreekanth V; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Han M; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Lim D; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Carpenter AE; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Flannick J; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Finucane H; Harvard Medical School, Boston, USA.
  • Haigis MC; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Claussnitzer M; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
  • Sheu E; Ludwig Center for Cancer Research at Harvard, Boston, MA 02115, USA.
  • Stevens B; Harvard Chan Advanced Multiomics Platform, Harvard T.H. Chan School of Public Health, Boston MA 02115 USA.
  • Wagner BK; Harvard Chan Advanced Multiomics Platform, Harvard T.H. Chan School of Public Health, Boston MA 02115 USA.
  • Choudhary A; Laboratory for Surgical and Metabolic Research, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Shaw JL; Broad Institute of MIT and Harvard, Cambridge, USA.
  • Pablo JL; Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Greka A; Broad Institute of MIT and Harvard, Cambridge, USA.
bioRxiv ; 2023 Feb 20.
Article em En | MEDLINE | ID: mdl-36865221
Cellular 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. Highlights: FALCON (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.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos