Bioactive dietary long-chain fatty acids: emerging mechanisms of action

Abstract

The plasma membranes of all eukaryotic cells contain heterogeneous self-organising intrinsically unstable liquid ordered domains or lipid assemblies in which key signal transduction proteins are localised. These assemblies are classified as 'lipid rafts' (10-200 nm), which are composed mostly of cholesterol and sphingolipid microdomains and therefore do not integrate well into the fluid phospholipid bilayers. In addition, caveolae represent a subtype of lipid raft macrodomain that form flask-shaped membrane invaginations containing structural proteins, i.e. caveolins. With respect to the diverse biological effects of long-chain PUFA, increasing evidence suggests that n-3 PUFA and perhaps conjugated fatty acids uniquely alter the basic properties of cell membranes. Because of its polyunsaturation, DHA and possibly conjugated linoleic acid are sterically incompatible with sphingolipid and cholesterol and, therefore, appear to alter lipid raft behaviour and protein function. The present review examines the evidence indicating that dietary sources of n-3 PUFA can profoundly alter the biochemical make up of lipid rafts/caveolae microdomains, thereby influencing cell signalling, protein trafficking and cell cytokinetics.

Figure 1. Nuclear receptor activation by conjugated linoleic acid

ER, endoplasmic reticulum; FABP, fatty acid binding proteins (molecular chaperone); PPAR, peroxisome proliferators-activated receptors; RXR, retinoid X receptors. CLA transactivates PPAR nuclear receptors, n-3 PUFA suppress NF-kB activation. All membranes incorporporate EPA, DHA and conjugated PUFA to different degrees.

Figure 2. Putative membrane microdomain altering properties of n-3 PUFA and CLA

Dietary DHA and CLA are incorporated into both the bulk phase of the plasma membrane as well as discrete heterogeneous cholesterol/sphingolipid-rich raft domains. This can alter plasma membrane organization of inner leaflets and the dynamic partitioning of transduction proteins, thereby modulating their function