Perspective: What Should I Eat to Maintain Membrane Lipid Rafts and Avoid Metabolic Disease?

Abstract

Discerning meaningful patterns in lipidomic studies of metabolic diseases is daunting. Consideration of changes in dietary lipids over the last 150 years and the effects of this variance on membrane raft formation provides a tool to better understand lipidomic data. In vitro, mixtures of low and high melting point lipids and cholesterol spontaneously form bilayers with heterologous areas of differing order, composition, and physical properties. Through dozens of studies, the general behavior of different lipid mixtures in phase separation has been mapped and displayed as ternary lipid mixture phase diagrams; areas that show both liquid order (Lo) and liquid disorder (Ld) allow raft formation (Figure 1). In vivo, ordered membrane areas composed of sterols, sphingolipids and proteins provide platforms necessary for a complex network of cellular signaling. Although there is controversy regarding the primacy of lipids versus proteins in organizing these signaling rafts, this perspective focuses on the role that variations in dietary lipids might play in raft formation. Comparison of dietary lipids in humans living before the agricultural revolution to those living in 21st century developed areas reveals major differences. Modern diets have: increased polyunsaturated fatty acids (PUFA) from vegetable oils, an increased ratio of omega 6:3 PUFA, increased trans fatty acids (TFA), and decreased cholesterol. Plotting these variations in dietary lipids on a ternary graph provides a framework to understand the theoretical effect of dietary lipid variance on phase separation and membrane behavior. For example, how might increased dietary TFA, a widely recognized risk factor in cardiovascular disease, disrupt raft formation? Substitution of TFA for PUFA at sn-2 in low melting point phospholipids would raise the melting point; substitution at sn-1 on sphingolipids would lower the melting point. Because disparity in the order of membrane domains is critical in the maintenance of phase separation, convergence of melting points of these compounds would thus impede raft formation (Figure 2). To compensate, incorporation of highly unsaturated PUFA to lower the melting point of non raft phospholipids, or incorporation of longer chain saturated fatty acids to raise the melting point of raft associated lipids would restore order differential and allow raft formation, but would require other changes to maintain optimal membrane viscosity. Elevated membrane PUFA increases oxidative damage and an elevated omega 6:3 ratio increases thrombosis and inflammation. Compared to cis forms, TFA phospholipids require eight times more cholesterol to be incorporated into a membrane; with reduced cholesterol diets, accommodation of TFAs into membranes would require stimulation of endogenous cholesterol synthesis. Increased membrane cholesterol also decreases permeability to oxygen. Because most fatty acids are incorporated into cell membranes unmodified from the form in which they were absorbed from the GI tract, changes in dietary lipids critically impact cell membrane composition. This example illustrates the theoretical impact of dietary lipids on raft formation and behavior as a means to understand lipidomic data and the pathophysiologic elements of dyslipidemia, oxidative stress, inflammation and cellular hypoxia.