n−3 PUFA and membrane microdomains: a new frontier in bioactive lipid research

doi:10.1016/j.jnutbio.2004.08.002

The Journal of Nutritional Biochemistry

Volume 15, Issue 11, November 2004, Pages 700-706

https://doi.org/10.1016/j.jnutbio.2004.08.002 Get rights and content

Abstract

In recent years, our understanding of the plasma membrane has changed considerably as our knowledge of lipid microdomains has expanded. Lipid microdomains include structures known as lipid rafts and caveolae, which are readily identified by their unique lipid constituents. Cholesterol, sphingolipids and phospholipids with saturated fatty acyl chain moieties are highly enriched in these lipid microdomains. Lipid rafts and caveolae have been shown to play an important role in the compartmentalization, modulation and integration of cell signaling. Therefore, these microdomains may have an influential role in human disease. Dietary n−3 polyunsaturated fatty acids (PUFA) ameliorate a number of human diseases including coronary heart disease, autoimmune and inflammatory disorders, diabetes, obesity and cancer, which has been generally linked to its membrane remodeling properties. Recent in vitro evidence suggests that perturbations in membrane composition alter the function of resident proteins and, consequently, cellular responses. This review examines the role of n−3 PUFA in modulating the lipid composition and functionality of lipid microdomains and its potential significance to human health.

Introduction

Dietary fat plays an important role in human health and disease. Fat is a source of energy, but it is also a vital structural component of cellular membranes and is involved in many important cell-signaling pathways. The latter two points are the focus of this review, which examines the role of dietary fats such as n−3 polyunsaturated fatty acids (PUFA) in modulating plasma membrane composition and cellular signaling in relation to lipid microdomains. Dietary fat is perceived to contribute negatively to many diseases such as heart disease, diabetes, obesity and cancer. In contrast, there is a growing body of evidence indicating a protective effect of n−3 PUFA; however, a comprehensive understanding of the mechanism(s) of action has yet to be elucidated [1], [2], [3]. The primary source of very long chain n−3 PUFA in the diet is derived from the consumption of cold-water fatty fish such as salmon and tuna. Fish are rich in two specific n−3 PUFA, eicosapentaenoic acid (EPA; 20:5 n−3) and docosahexaenoic acid (DHA; 22:6 n−3). The broad health benefits of n−3 PUFA in many diseases, that is, heart disease, diabetes, obesity, cancer and autoimmune and inflammatory disorders, suggest that a common fundamental mechanism is involved. We suggest that lipid microdomains may be a novel modality mediating the biological effects of n−3 PUFA across a number of diverse organ systems.

Section snippets

Lipid rafts, caveolae and biological relevance

The once simple fluid mosaic model of the plasma membrane has evolved significantly and is now known to contain specialized microdomains such as lipid rafts and caveolae (Fig. 1). Other common names include detergent-resistant membranes (DRMs) and detergent-insoluble glycosphingolipids. These descriptors reflect the insolubility of lipid domains in cold nonionic detergents. Our understanding of these microdomains has grown tremendously in the last several years [4]. The biochemical

In vivo effect of n−3 PUFA on T-cell lipid rafts

Early in vitro observations suggest that lipid rafts are sensitive to bilayer remodeling by manipulating the type of PUFA provided to cells in culture. PUFA incorporation into membrane lipids in a Jurkat T-cell line selectively modified lipid rafts and suppressed signal transduction by displacement of Src family kinases Lck and Fyn [34], [35] and LAT [36] from lipid rafts. Similarly, in COS-1 cells, the localization of Fyn was shown to be inhibited by arachidonic acid (AA), EPA and DHA [37]. In

n−3 PUFA alter intestinal caveolae lipid composition and resident protein localization in vivo

In an in vivo model, Ma et al. [42] have recently shown that dietary n−3 PUFA markedly alter the lipid composition of colonic caveolae/lipid rafts in mice fed with fish oil enriched with EPA and DHA, relative to mice fed with an n−6 PUFA (control) diet primarily containing linoleic acid (18:2 n−6). The n−3 fatty acids, EPA and DHA, from fish oil were incorporated into the fatty acyl groups of caveolae phospholipids and decreased the caveolar content of cholesterol and caveolin-1, the major

Mechanism of n−3 PUFA action

n−3 PUFA incorporation into lipid microdomains has been shown to coincide with reductions in cholesterol or sphingomyelin content therein, which are important in the assembly of a liquid-ordered phase structure. n−3 PUFA-induced caveolar cholesterol reduction may be explained, at least in part, by poor solubility of cholesterol in phospholipids enriched with long-chain n−3 PUFA. The incompatibility between the highly flexible, very long chain n−3 PUFA (EPA and DHA) and the rigid sterol moiety

Future directions

As we expand our knowledge of principles and determinants of the lateral organization of lipid microdomains and their biological relevance, our understanding of the role and modulatory effect of n−3 PUFA in lipid microdomains will also significantly advance. It has been appreciated that experimental outcomes regarding biochemical isolation of microdomains vary depending on the isolation method, choice of detergent and cell type [49], suggesting the presence of heterogeneous raft populations [50]

Conclusion

Overall, these findings provide compelling evidence demonstrating that dietary sources of n−3 PUFA can profoundly alter the biochemical makeup of lipid rafts and caveolae membrane microdomains, thereby influencing cellular signaling (Fig. 2). These observations suggest that lipid rafts and caveolae are likely molecular targets through which long-chain n−3 PUFA modulate diverse biological systems and reduce the incidence and severity of human diseases.

Acknowledgments

This work was supported in part by the American Institute for Cancer Research grant 03A038, National Institutes of Health grants CA-59034, P30-ES-09106 and DK53055 and U.S. Department of Agriculture grant 2003-35200-13338. David W.L. Ma is a recipient of postdoctoral fellowships from the Natural Sciences and Engineering Research Council of Canada, the Alberta Heritage for Medical Research Foundation.

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¹: Present address. Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 3E2.

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n−3 PUFA and membrane microdomains: a new frontier in bioactive lipid research

Abstract

Introduction

Section snippets

Lipid rafts, caveolae and biological relevance

In vivo effect of n−3 PUFA on T-cell lipid rafts

n−3 PUFA alter intestinal caveolae lipid composition and resident protein localization in vivo

Mechanism of n−3 PUFA action

Future directions

Conclusion

Acknowledgments

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