Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidity
- University of Gothenburg, Sweden
- University of Helsinki, Finland
Abstract
The human AdipoR1 and AdipoR2 proteins, as well as their C. elegans homolog PAQR-2, protect against cell membrane rigidification by exogenous saturated fatty acids by regulating phospholipid composition. Here, we show that mutations in the C. elegans gene acs-13 help to suppress the phenotypes of paqr-2 mutant worms, including their characteristic membrane fluidity defects. acs-13 encodes a homolog of the human acyl-CoA synthetase ACSL1, and localizes to the mitochondrial membrane where it likely activates long chains fatty acids for import and degradation. Using siRNA combined with lipidomics and membrane fluidity assays (FRAP and Laurdan dye staining) we further show that the human ACSL1 potentiates lipotoxicity by the saturated fatty acid palmitate: silencing ACSL1 protects against the membrane rigidifying effects of palmitate and acts as a suppressor of AdipoR2 knockdown, thus echoing the C. elegans findings. We conclude that acs-13 mutations in C. elegans and ACSL1 knockdown in human cells prevent lipotoxicity by promoting increased levels of polyunsaturated fatty acid-containing phospholipids.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. The lipidomics data is provided as a supplementary table.
Article and author information
Author details
Funding
Vetenskapsrådet (Dnr: 2016-03676)
- Marc Pilon
Cancerfonden (Dnr 16 0693)
- Marc Pilon
Carl Tryggers Stiftelse för Vetenskaplig Forskning (CTS 16:365)
- Marc Pilon
Diabetesfonden (DIA2016-109)
- Marc Pilon
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Tobias C Walther, Howard Hughes Medical Institute, University of California, San Francisco, United States
Version history
- Received: April 16, 2019
- Accepted: November 23, 2019
- Accepted Manuscript published: November 26, 2019 (version 1)
- Version of Record published: December 9, 2019 (version 2)
Copyright
© 2019, Ruiz et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidity
eLife 8:e47733.
https://doi.org/10.7554/eLife.47733
