Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidity
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 pa...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/47733 |
| _version_ | 1828382865561223168 |
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| author | Mario Ruiz Rakesh Bodhicharla Marcus Ståhlman Emma Svensk Kiran Busayavalasa Henrik Palmgren Hanna Ruhanen Jan Boren Marc Pilon |
| author_facet | Mario Ruiz Rakesh Bodhicharla Marcus Ståhlman Emma Svensk Kiran Busayavalasa Henrik Palmgren Hanna Ruhanen Jan Boren Marc Pilon |
| author_sort | Mario Ruiz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T04:39:57Z |
| format | Article |
| id | doaj.art-a25d9e37660c4923ac583e6d2a9c3976 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:39:57Z |
| publishDate | 2019-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-a25d9e37660c4923ac583e6d2a9c39762022-12-22T02:01:55ZengeLife Sciences Publications LtdeLife2050-084X2019-11-01810.7554/eLife.47733Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidityMario Ruiz0Rakesh Bodhicharla1Marcus Ståhlman2https://orcid.org/0000-0002-4202-0339Emma Svensk3Kiran Busayavalasa4Henrik Palmgren5Hanna Ruhanen6Jan Boren7Marc Pilon8https://orcid.org/0000-0003-3919-2882Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, SwedenDepartment of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, SwedenDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg, Gothenburg, SwedenDepartment of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, SwedenDepartment of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, SwedenMetabolism BioScience, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SwedenHelsinki University Lipidomics Unit, Helsinki Institute for Life Science, Helsinki, Finland; Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, FinlandDepartment of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg, Gothenburg, SwedenDepartment of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, SwedenThe 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.https://elifesciences.org/articles/47733phospholipidscell membraneacyl-coA synthetaseadiponectin receptorforward geneticslipidomics |
| spellingShingle | Mario Ruiz Rakesh Bodhicharla Marcus Ståhlman Emma Svensk Kiran Busayavalasa Henrik Palmgren Hanna Ruhanen Jan Boren Marc Pilon Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidity eLife phospholipids cell membrane acyl-coA synthetase adiponectin receptor forward genetics lipidomics |
| title | Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidity |
| title_full | Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidity |
| title_fullStr | Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidity |
| title_full_unstemmed | Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidity |
| title_short | Evolutionarily conserved long-chain Acyl-CoA synthetases regulate membrane composition and fluidity |
| title_sort | evolutionarily conserved long chain acyl coa synthetases regulate membrane composition and fluidity |
| topic | phospholipids cell membrane acyl-coA synthetase adiponectin receptor forward genetics lipidomics |
| url | https://elifesciences.org/articles/47733 |
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