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

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

The Mina and Everard Goodman Faculty of Life Sciences - at Bar-Ilan University

Bar-Ilan University

Research output: Contribution to journal › Article › peer-review

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 language	English
Pages (from-to)	887-905.e11
Journal	Cell Metabolism
Volume	35
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2023.03.018
State	Published - 2 May 2023

Keywords

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

All Science Journal Classification (ASJC) codes

Physiology
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cmet.2023.03.018

Cite this

Wieder, N., Fried, J. C., Kim, C., Sidhom, E. H., Brown, M. R., Marshall, J. L., Arevalo, C., Dvela-Levitt, M., Kost-Alimova, M., Sieber, J., Gabriel, K. R., Pacheco, J., Clish, C., Abbasi, H. S., Singh, S., Rutter, J. C., Therrien, M., Yoon, H., Lai, Z. W., ... Greka, A. (2023). FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity. Cell Metabolism, 35(5), 887-905.e11. https://doi.org/10.1016/j.cmet.2023.03.018

@article{be4005b643d84e24a6f755eb75687f4f,

title = "FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity",

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",

author = "Nicolas Wieder and Fried, {Juliana Coraor} and Choah Kim and Sidhom, {Eriene Heidi} and Brown, {Matthew R.} and Marshall, {Jamie L.} and Carlos Arevalo and Moran Dvela-Levitt and Maria Kost-Alimova and Jonas Sieber and Gabriel, {Katlyn R.} and Julian Pacheco and Clary Clish and Abbasi, {Hamdah Shafqat} and Shantanu Singh and Rutter, {Justine C.} and Martine Therrien and Haejin Yoon and Lai, {Zon Weng} and Aaron Baublis and Renuka Subramanian and Ranjan Devkota and Jonnell Small and Vedagopuram Sreekanth and Myeonghoon Han and Donghyun Lim and Carpenter, {Anne E.} and Jason Flannick and Hilary Finucane and Haigis, {Marcia C.} and Melina Claussnitzer and Eric Sheu and Beth Stevens and Wagner, {Bridget K.} and Amit Choudhary and Shaw, {Jillian L.} and Pablo, {Juan Lorenzo} and Anna Greka",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = may,

day = "2",

doi = "10.1016/j.cmet.2023.03.018",

language = "الإنجليزيّة",

volume = "35",

pages = "887--905.e11",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

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Wieder, N, Fried, JC, Kim, C, Sidhom, EH, Brown, MR, Marshall, JL, Arevalo, C, Dvela-Levitt, M, Kost-Alimova, M, Sieber, J, Gabriel, KR, Pacheco, J, Clish, C, Abbasi, HS, Singh, S, Rutter, JC, Therrien, M, Yoon, H, Lai, ZW, Baublis, A, Subramanian, R, Devkota, R, Small, J, Sreekanth, V, Han, M, Lim, D, Carpenter, AE, Flannick, J, Finucane, H, Haigis, MC, Claussnitzer, M, Sheu, E, Stevens, B, Wagner, BK, Choudhary, A, Shaw, JL, Pablo, JL & Greka, A 2023, 'FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity', Cell Metabolism, vol. 35, no. 5, pp. 887-905.e11. https://doi.org/10.1016/j.cmet.2023.03.018

TY - JOUR

T1 - FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity

AU - Wieder, Nicolas

AU - Fried, Juliana Coraor

AU - Kim, Choah

AU - Sidhom, Eriene Heidi

AU - Brown, Matthew R.

AU - Marshall, Jamie L.

AU - Arevalo, Carlos

AU - Dvela-Levitt, Moran

AU - Kost-Alimova, Maria

AU - Sieber, Jonas

AU - Gabriel, Katlyn R.

AU - Pacheco, Julian

AU - Clish, Clary

AU - Abbasi, Hamdah Shafqat

AU - Singh, Shantanu

AU - Rutter, Justine C.

AU - Therrien, Martine

AU - Yoon, Haejin

AU - Lai, Zon Weng

AU - Baublis, Aaron

AU - Subramanian, Renuka

AU - Devkota, Ranjan

AU - Small, Jonnell

AU - Sreekanth, Vedagopuram

AU - Han, Myeonghoon

AU - Lim, Donghyun

AU - Carpenter, Anne E.

AU - Flannick, Jason

AU - Finucane, Hilary

AU - Haigis, Marcia C.

AU - Claussnitzer, Melina

AU - Sheu, Eric

AU - Stevens, Beth

AU - Wagner, Bridget K.

AU - Choudhary, Amit

AU - Shaw, Jillian L.

AU - Pablo, Juan Lorenzo

AU - Greka, Anna

PY - 2023/5/2

Y1 - 2023/5/2

N2 - 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.

AB - 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.

KW - CMIP

KW - GWAS

KW - erucic acid

KW - kidney

KW - lipidomics

KW - microglia

KW - obesity

KW - pancreatic β cell

KW - transcriptomics

KW - type 2 diabetes

UR - http://www.scopus.com/inward/record.url?scp=85153589952&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2023.03.018

DO - 10.1016/j.cmet.2023.03.018

M3 - مقالة

C2 - 37075753

SN - 1550-4131

VL - 35

SP - 887-905.e11

JO - Cell Metabolism

JF - Cell Metabolism

IS - 5

ER -

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

Abstract

Keywords

All Science Journal Classification (ASJC) codes

UN SDGs

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