Effects Of Oxidative Stress, Hyperglycemia, And Hypercholesterolemia On Membrane Structural Organization And The Interactions Of Omega-3 Fatty Acids

Cellular membranes are dynamic structures that play a critical role in facilitating and maintaining cell function. Membrane structure and fluidity are dependent on relative lipid (including cholesterol) and protein levels, which are known to change with aging and in different disease processes. The plasma membrane is organized into microdomains that have distinct biophysical and biochemical characteristics that mediate specific cellular activities. Lipid rafts, for example, sequester a variety of important intracellular signaling proteins and directly regulate their activity. In response to changes in membrane structure, some proteins can migrate between lipid-disordered, cholesterol-poor membrane regions and lipid-ordered, cholesterol-rich domains to differentially affect intracellular signaling. Cholesterol crystalline domains have been observed to form in vascular cells and in various membrane model systems when exposed to disease-like perturbations, including oxidative stress, hyperglycemia, and hypercholesterolemia. Membrane cholesterol enrichment and domain formation is believed to precipitate extracellular changes, such as crystal deposition in the atheroma with subsequent plaque destabilization and thrombus formation. Marine-derived long chain polyunsaturated omega-3 fatty acids have been shown to affect membrane lipid structure and fluidity. Both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have potent antioxidant effects in model membranes and human lipoproteins, but the sustainability of these effects appear to vary under certain conditions, and EPA and DHA seem to differentially affect membrane fluidity, cholesterol domain formation, and membrane function. In this chapter, we will discuss how disease-like conditions induce structural changes to the cell membrane that negatively affect cellular function and potentiate the atherogenic process, as well as how lipid components within the membrane may alter these effects.