NMR STUDIES OF WEAKLY POLAR LIPIDS

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Cholesteryl esters (CE), diacylglycerols (DAG) and triacylglycerols (TAG) are important lipids in both normal and abnormal human physiology. CE are intermediates in cholesterol transport and metabolism and a major chemical component of atherosclerotic plaques; 1,2 DAG are 'second messengers' in many cellular signal transduction processes; and TAG are the main storage form of body fats. These water-insoluble, neutral molecules, which readily form separate phases, also partition to limited extents into phospholipid lamellar structures because of their weak polarity. A working hypothesis of this proposal is that interfacially-located weakly polar lipids interact with enzymes, transport proteins and membrane proteins, and that interfacial properties such as extent of solubility, conformation and mobility are key determinants of these interactions. A general goal is to elucidate physical properties that explain lipid transport and metabolism and that will provide new diagnostic and treatment methods for human disease. Interfacial properties of these lipids will be probed by high resolution, magic angle spinning (MAS), and solid state NMR methods for 13C, 1H and 31P nuclei, in conjunction with other appropriate physical techniques. These studies will examine native, biological lipids (with 13C-carbonyl enrichment in some cases) and the widely used, non- metabolizable CE analogue, cholesterol oleyl ether. MAS and solid state NMR methods will examine interfacial properties of weakly polar lipids in multilamellar systems which model membranes or phospholipid monolayer surfaces with low curvature, and high resolution methods will examine a model system for highly curved surfaces (small unilamellar vesicles). A new methodology, based on 13C chemical shifts, will test what interaction properties influence transport of CE and TAG by carrier proteins. The competition of medium chain TAG with CE and long emulsion particles suitable for parenteral feeding to patients with impaired TAG metabolism. Bulk properties of CE are important in atherogenesis, and the structural organization and dynamics of CE and other lipids in atherosclerotic lesions of cholesterol-fed rabbits will be examined by high resolution and MAS NMR. NMR data will be carefully correlated with chemical, microscopic and calorimetric data on the same sample. Such studies are essential precursors to future high resolution and imaging NMR studies on humans.