Polyunsaturated fatty acid–cholesterol interactions: Domain formation in membranes
Open accessAbstract
Polyunsaturated fatty acids (PUFA) constitute an influential group of molecules that promote health by an as yet unknown mechanism. They are structurally distinguished from less unsaturated fatty acids by the presence of a repeating =CH-CH(2)-CH= unit that produces an extremely flexible chain rapidly reorienting through conformational states. The most highly unsaturated case in point is docosahexaenoic acid (DHA) with 6 double bonds. This review will summarize how the high disorder of DHA affects the properties of the membrane phospholipids into which the PUFA incorporates, focusing upon the profound impact on the interaction with cholesterol. Results obtained with model membranes using an array of biophysical techniques will be presented. They demonstrate DHA and the sterol possesses a mutual aversion that drives the lateral segregation of DHA-containing phospholipids into highly disordered domains away from cholesterol. These domains are compositionally and organizationally the opposite of lipid rafts, the ordered domain enriched in predominantly saturated sphingolipids "glued" together by cholesterol that is believed to serve as the platform for signaling proteins. We hypothesize that DHA-rich domains also form in the plasma membrane and are responsible, in part, for the diverse range of health benefits associated with DHA.
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In KO astrocytes, the membrane phospholipid profile favored highly unsaturated phosphatidylcholine species and contained less sphingomyelin, rendering the membrane structurally incompatible with cholesterol.
“In KO astrocytes, the membrane PL profile favored the highly unsaturated PC species and contained less SM, rendering the membrane structurally incompatible with cholesterol44.”
From An iPSC-derived astrocyte model of fragile X syndrome exhibits dysregulated cholesterol homeostasis (2023) · cites this paper as [44]
Section 5 (‘DHA has an aversion for cholesterol’; page unavailable) reports reduced cholesterol solubility in highly polyunsaturated PC membranes, and Section 6 describes cholesterol-poor domains formed by such lipids. The paper does not report a phospholipid profile for KO astrocytes or show that their membranes contain less sphingomyelin; its model-membrane findings do not establish that those astrocyte membranes are structurally incompatible with cholesterol. (LLM, conf=0.88)
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- Authors
- Wassall, S. R., & Stillwell, W.
- Affiliations
- Indiana University – Purdue University Indianapolis (US)
- Corresponding author
- Wassall, Stephen R.
- Venue
- Biochimica et Biophysica Acta (BBA) - Biomembranes
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 1788
- Issue
- 1
- Pages
- 24-32
- ISSN
- 0005-2736 (ISSN-L)
- OpenAlex
- W2004029325
- Cited by
- 292
- References
- 96
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 18 · 2023: 8 · 2022: 22 · 2021: 25 · 2020: 14 · 2019: 12 · 2018: 29 · 2017: 16 · 2016: 30 · 2015: 18 · 2014: 14 · 2013: 18 · 2012: 19
- FWCI
- 0.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Biomembranes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Indiana University-Purdue University Indianapolis
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- polyunsaturated fatty acids, docosahexaenoic acid, cholesterol, lipid rafts, membrane domain formation, lateral segregation, model membranes, plasma membrane, membrane fluidity
- MeSH terms
- Animals, Cholesterol, Docosahexaenoic Acids, Fatty Acids, Unsaturated, Humans, Hydrogen Bonding, Membranes, Models, Biological, Models, Molecular, Oleic Acids, Molecular Structure, Membrane Microdomains
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