Dietary Fats Remodel Plasma Membrane Lipidome and Physical Properties to Regulate Phase Separation in Biological Membranes

Abstract

The spatial organization of biological membranes is crucial for their extensive functionality. One example of such organization is the partitioning of mammalian plasma membranes (PMs) into lipid-driven ordered domains termed membrane rafts. While the physicochemical interactions responsible for raft formation are clearly established, the specific properties and biological consequences of these domains remain unclear. In particular, little is known about how the properties of raft domains are regulated, either by endogenous mechanisms or exogenous perturbations. In this context, an intriguing question concerns the effect of dietary fats on the lipid composition, biophysical properties, and ultimate function of membrane domains. Here, we investigate the consequences of the ω-3 polyunsaturated fatty acid docosohexaenoic acid (DHA) on the biochemical and biophysical properties of the mammalian PM. By detailed lipidomic analysis, we observe that DHA is robustly incorporated into specific PM lipids leading to wholesale remodeling of the lipidome, with saturated lipids and cholesterol up-regulated as a homeoviscous compensatory response to the disordering effect of polyunsaturated lipids. The combined effect of DHA incorporation and compensatory response result in biophysical remodeling of the PM, which we address in membrane model systems ranging from coarse-grained molecular dynamics simulations to intact PMs isolated from live cells. In all systems, DHA-containing lipids promote liquid-liquid phase separation by disordering non-raft domains and thereby increasing the differences between coexisting raft and non-raft phases. This relationship between interdomain disparity and stability of phase separation holds for a variety of perturbations, including manipulation of cholesterol levels and treatment by exogenous amphiphiles, suggesting it as a general design feature of the organization of biological membranes.