The principal aim of this program project is to delineate the processes that give rise to the multiple subclasses of human plasma lipoproteins, thereby to better understand the influence of genetic and environmental factors on plasma lipid transport and the development of atherosclerosis. A wide range of scientific disciplines and experimental approaches will be used, including human and molecular genetics, metabolism, cell biology, biochemistry, biophysics, mathematics and statistics. The program is organized into five highly interactive Projects and three Core units which provide support services used by each of the projects. Project 1 is aimed at determining the influence of genetic and metabolic factors on the distribution and properties of human low density lipoprotein (LDL) subclasses and to refine genetic models for the heritability of lipoprotein subclass phenotypes. The structural, metabolic, and genetic implications of recently demonstrated differences in glycosylation of apolipoprotein (apo) B across the LDL particle spectrum will be investigated in detail. In Project 2, model lipoprotein systems will be used to define the physical-chemical and metabolic bases for speciation, remodeling and function of nascent and plasma apo-specific high density lipoprotein (HDL) subpopulations. A major focus will be on the influence of triglyceride- rich lipoprotein metabolism on the formation and properties of HDL subclasses, and on their function in intravascular and extravascular cholesterol transport. Project 3 further examines the critical link between triglyceride-rich lipoproteins and the formation and metabolism of LDL and HDL subclasses by investigating the role of lipolysis products in mediating physical interactions and transfers among lipoprotein particles. Specific processes to be studied include the direct removal of surface lipids from remnants by HDL proteins, the binding of LDL to remnants, and the roles of these processes in forming HDL and LDL subclasses and in influencing remnant metabolism. In Project 4, the in vivo origins of HDL subclasses, their structural and regulatory determinants, and their influence on lipoprotein metabolism and atherosclerosis will be investigated in transgenic mice carrying the human genes for apoAI and apoAII, the major HDL protein constituents. Cell culture systems will be employed in Project 5 to delineate the cellular origins of apo-specific HDL subpopulations and to study the influence of apoAI and apoAII gene expression on this process. Hepatic cell cultures will also be used to further investigate the relationship of varying apoB glycosylation with LDL subclass formation and metabolism. The Lipoprotein Analysis Core will provide standardized measurements of lipids, lipoproteins, and apolipoproteins for all Projects, and will also serve as a resource for specialized analytic and preparative procedures. The Computation and Statistics Core will support data acquisition, analysis and storage, while the Administrative Core will oversee and coordinate all scientific and support activities, including the clinic. In summary, this Program Project provides an integrated, multidisciplinary approach to the understanding of mechanisms influencing the properties, functions, interrelationships, and clinical significance of lipoprotein subclasses.
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