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Title: Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation

Abstract

Docosahexaenoic acid (DHA, 22:6) is an n–3 polyunsaturated fatty acid (n–3 PUFA) that influences immunological, metabolic, and neurological responses through complex mechanisms. One structural mechanism by which DHA exerts its biological effects is through its ability to modify the physical organization of plasma membrane signaling assemblies known as sphingomyelin/cholesterol (SM/chol)-enriched lipid rafts. In this work, we studied how DHA acyl chains esterified in the sn-2 position of phosphatidylcholine (PC) regulate the formation of raft and non-raft domains in mixtures with SM and chol on differing size scales. Coarse grained molecular dynamics simulations showed that 1-palmitoyl-2-docosahexaenoylphosphatylcholine (PDPC) enhances segregation into domains more than the monounsaturated control, 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC). Solid state 2H NMR and neutron scattering experiments provided direct experimental evidence that substituting PDPC for POPC increases the size of raft-like domains on the nanoscale. Confocal imaging of giant unilamellar vesicles with a non-raft fluorescent probe revealed that POPC had no influence on phase separation in the presence of SM/chol whereas PDPC drove strong domain segregation. Lastly, monolayer compression studies suggest that PDPC increases lipid-lipid immiscibility in the presence of SM/chol compared to POPC. Collectively, the data across model systems provide compelling support for the emerging model that DHA acyl chains ofmore » PC lipids tune the size of lipid rafts, which has potential implications for signaling networks that rely on the compartmentalization of proteins within and outside of rafts.« less

Authors:
; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1567874
Alternate Identifier(s):
OSTI ID: 1566959
Grant/Contract Number:  
DEAC05-00OR22725; AC05-00OR22725
Resource Type:
Published Article
Journal Name:
Biochimica et Biophysica Acta. Biomembranes
Additional Journal Information:
Journal Name: Biochimica et Biophysica Acta. Biomembranes Journal Volume: 1860 Journal Issue: 10; Journal ID: ISSN 0005-2736
Publisher:
Elsevier
Country of Publication:
Netherlands
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Lipid rafts; Polyunsaturated fatty acids; Biomimetic membranes; Cholesterol; Docosahexaenoic acid (DHA)

Citation Formats

Wassall, Stephen R., Leng, Xiaoling, Canner, Samuel W., Pennington, Edward Ross, Kinnun, Jacob J., Cavazos, Andres T., Dadoo, Sahil, Johnson, Dylan, Heberle, Frederick A., Katsaras, John, and Shaikh, Saame Raza. Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation. Netherlands: N. p., 2018. Web. doi:10.1016/j.bbamem.2018.04.016.
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Wassall, Stephen R., Leng, Xiaoling, Canner, Samuel W., Pennington, Edward Ross, Kinnun, Jacob J., Cavazos, Andres T., Dadoo, Sahil, Johnson, Dylan, Heberle, Frederick A., Katsaras, John, & Shaikh, Saame Raza. Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation. Netherlands. https://doi.org/10.1016/j.bbamem.2018.04.016
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Wassall, Stephen R., Leng, Xiaoling, Canner, Samuel W., Pennington, Edward Ross, Kinnun, Jacob J., Cavazos, Andres T., Dadoo, Sahil, Johnson, Dylan, Heberle, Frederick A., Katsaras, John, and Shaikh, Saame Raza. Mon . "Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation". Netherlands. https://doi.org/10.1016/j.bbamem.2018.04.016.
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@article{osti_1567874,
title = {Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation},
author = {Wassall, Stephen R. and Leng, Xiaoling and Canner, Samuel W. and Pennington, Edward Ross and Kinnun, Jacob J. and Cavazos, Andres T. and Dadoo, Sahil and Johnson, Dylan and Heberle, Frederick A. and Katsaras, John and Shaikh, Saame Raza},
abstractNote = {Docosahexaenoic acid (DHA, 22:6) is an n–3 polyunsaturated fatty acid (n–3 PUFA) that influences immunological, metabolic, and neurological responses through complex mechanisms. One structural mechanism by which DHA exerts its biological effects is through its ability to modify the physical organization of plasma membrane signaling assemblies known as sphingomyelin/cholesterol (SM/chol)-enriched lipid rafts. In this work, we studied how DHA acyl chains esterified in the sn-2 position of phosphatidylcholine (PC) regulate the formation of raft and non-raft domains in mixtures with SM and chol on differing size scales. Coarse grained molecular dynamics simulations showed that 1-palmitoyl-2-docosahexaenoylphosphatylcholine (PDPC) enhances segregation into domains more than the monounsaturated control, 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC). Solid state 2H NMR and neutron scattering experiments provided direct experimental evidence that substituting PDPC for POPC increases the size of raft-like domains on the nanoscale. Confocal imaging of giant unilamellar vesicles with a non-raft fluorescent probe revealed that POPC had no influence on phase separation in the presence of SM/chol whereas PDPC drove strong domain segregation. Lastly, monolayer compression studies suggest that PDPC increases lipid-lipid immiscibility in the presence of SM/chol compared to POPC. Collectively, the data across model systems provide compelling support for the emerging model that DHA acyl chains of PC lipids tune the size of lipid rafts, which has potential implications for signaling networks that rely on the compartmentalization of proteins within and outside of rafts.},
doi = {10.1016/j.bbamem.2018.04.016},
journal = {Biochimica et Biophysica Acta. Biomembranes},
number = 10,
volume = 1860,
place = {Netherlands},
year = {Mon Oct 01 00:00:00 EDT 2018},
month = {Mon Oct 01 00:00:00 EDT 2018}
}
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https://doi.org/10.1016/j.bbamem.2018.04.016
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