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 Baublis; Renuka 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

doi:10.1016/j.cmet.2023.03.018

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

Cell Metab. 2023 May 2;35(5):887-905.e11. doi: 10.1016/j.cmet.2023.03.018. Epub 2023 Apr 18.

Authors

Nicolas Wieder¹, Juliana Coraor Fried², Choah Kim², Eriene-Heidi Sidhom², Matthew R Brown³, Jamie L Marshall³, Carlos Arevalo³, Moran Dvela-Levitt⁴, Maria Kost-Alimova³, Jonas Sieber⁵, Katlyn R Gabriel³, Julian Pacheco³, Clary Clish³, Hamdah Shafqat Abbasi³, Shantanu Singh³, Justine C Rutter⁶, Martine Therrien³, Haejin Yoon⁷, Zon Weng Lai⁸, Aaron Baublis⁸, Renuka Subramanian⁹, Ranjan Devkota¹⁰, Jonnell Small¹¹, Vedagopuram Sreekanth¹², Myeonghoon Han³, Donghyun Lim³, Anne E Carpenter³, Jason Flannick¹³, Hilary Finucane¹⁴, Marcia C Haigis¹⁵, Melina Claussnitzer¹⁶, Eric Sheu⁹, Beth Stevens¹⁷, Bridget K Wagner¹⁰, Amit Choudhary¹⁸, Jillian L Shaw³, Juan Lorenzo Pablo³, Anna Greka¹⁹

Affiliations

¹ 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.
² 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.
³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ 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.
⁵ Department of Endocrinology, Metabolism and Cardiovascular Systems, University of Fribourg, Fribourg, Switzerland.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02115, USA.
⁷ Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Ludwig Center for Cancer Research at Harvard, Boston, MA 02115, USA.
⁸ Harvard Chan Advanced Multiomics Platform, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
⁹ Laboratory for Surgical and Metabolic Research, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹⁰ 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.
¹¹ 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.
¹² 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.
¹³ 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.
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytic and Translational Genetics Unit, Mass General Hospital, Boston, MA 02114, USA.
¹⁵ 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.
¹⁶ 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.
¹⁷ 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.
¹⁸ 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.
¹⁹ 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.

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.

Keywords: CMIP; GWAS; erucic acid; kidney; lipidomics; microglia; obesity; pancreatic β cell; transcriptomics; type 2 diabetes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Biology
Diabetes Mellitus, Type 2*
Fatty Acids
Fatty Acids, Nonesterified* / metabolism
Humans
Signal Transduction

Substances

Fatty Acids, Nonesterified
Fatty Acids

Abstract

Publication types

MeSH terms

Substances

Grants and funding