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Cell Chem Biol. 2019 Mar 21;26(3):420-432.e9. doi: 10.1016/j.chembiol.2018.11.016. Epub 2019 Jan 24.

Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State.

Author information

1
Department of Biology, Stanford University, Stanford, CA 94305, USA.
2
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
3
Departments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
4
Departments of Chemistry and Medicine, Washington University, St. Louis, MO 63130, USA.
5
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Departments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
6
Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: sjdixon@stanford.edu.

Abstract

The initiation and execution of cell death can be regulated by various lipids. How the levels of environmental (exogenous) lipids impact cell death sensitivity is not well understood. We find that exogenous monounsaturated fatty acids (MUFAs) potently inhibit the non-apoptotic, iron-dependent, oxidative cell death process of ferroptosis. This protective effect is associated with the suppression of lipid reactive oxygen species (ROS) accumulation at the plasma membrane and decreased levels of phospholipids containing oxidizable polyunsaturated fatty acids. Treatment with exogenous MUFAs reduces the sensitivity of plasma membrane lipids to oxidation over several hours. This effect requires MUFA activation by acyl-coenzyme A synthetase long-chain family member 3 (ACSL3) and is independent of lipid droplet formation. Exogenous MUFAs also protect cells from apoptotic lipotoxicity caused by the accumulation of saturated fatty acids, but in an ACSL3-independent manner. Our work demonstrates that ACSL3-dependent MUFA activation promotes a ferroptosis-resistant cell state.

KEYWORDS:

GPX4; MUFAs; cell death; ferroptosis; iron; lipid ROS; lipid droplet; lipotoxicity; oleate

PMID:
30686757
PMCID:
PMC6430697
[Available on 2020-03-21]
DOI:
10.1016/j.chembiol.2018.11.016

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