The steady state levels of plasma cholesterol and triglyceride must be closely related to the rates of entry into plasma, and removal from plasma, of the lipoproteins that transport these lipids. We have, therefore, focused on the kinetics of the metabolism of apolipoprotein (apo)B, the major, stable structural protein in very low (VLDL), intermediate (IDL) and low density lipoproteins (LDL). In the present application we propose to extend our previous studies to address the heterogeneous nature of these major lipoprotein (LP) classes by (1) isolating apo- specific LP subclasses that are enriched-in and deficient-in a particular apo. These subclasses, particularly those in VLDL, will be characterized and the metabolism of apoB in each subclass determined. ApoE-enriched and apoE-deficient VLDL subclasses will be studied first, followed by investigations of apoCIII- enriched and deficient VLDL subclasses; (2) characterizing VLDL subclasses according to the expression of specific apo-epitopes on the surface of particles in those subclasses. Monoclonal antibodies (mabs) directed at physiologically relevant domains (eg) an anti-apoB mab that recognizes the LDL binding domain of apoB, will be used to relate the """"""""functional"""""""" composition of LP subclasses to the kinetics of apoB in those LP populations. We will also continue previous studies of apoCIII and apoAI metabolism, focusing on the regulation of plasma high density lipoprotein (HDL) concentrations. We propose that reduced apoCIII production results in accelerated apoAI catabolism and low HDL levels. We will study apoCIII metabolism in normal subjects and in subjects with hypoalphalipoproteinemia. We will also explore the relationship between VLDL and HDL metabolism in subjects with familial combined hyperlipoproteinemia and familial hypertriglyceridemia. These subjects will have simultaneous studies of VLDL and HDL metabolism when they are hypertriglyceridemic and when they are normal. These studies will significantly increase our understanding of VLDL heterogeneity and hypoalphalipoproteinemia. Both VLDL and HDL may be intimately involved in the atherogenic process, and information generated by these studies should impact on our clinical approach to lipid disorders and to atherosclerosis.
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