Plasma lipoproteins play important roles in the release of lipids from liver, in the transport of lipids through plasma, and in the absorption of lipid from the gastrointestinal tract. The concentrations of lipoproteins in plasma depend upon their rates of secretion into plasma (input) relative to rates of catabolism (output). Both input and output rates may be regulated by genetically determined metabolic controls. Input is affected by factors such as diet, hormones, and the metabolic state of the animal and may be limited by the availability of the apolipoproteins. Output depends upon at least two enzymes and a number of "cofactor" peptides which form part of the lipoproteins themselves, i.e., the apolipoproteins. Thus, the peptide moieties of lipoproteins are important in the synthesis, structure and catabolism of lipoproteins. One of the objectives of this research is to study the overall process of lipoprotein production and the effects of metabolic and hormonal perturbations on this process. The isolated perfused livers of normal rats and ras subjected to various metabolic perturbations, will be used in conjunction with procedures (a) to characterize rates of secretion and density distributions of apoproteins, and (b) to characterize the apoprotein compositions of isolated lipoproteins. These procedures include ultracentrifugation, electron microscopy, and electrophoretic procedures and radioimmunoassays for apoproteins. Another aim is to describe the intracellular processes of lipoprotein synthesis and assembly, specifically to localize where in the cell, in relation to each other, various apoproteins are synthesized, and where lipid and apoprotein assembly occurs. Immunohistochemical techniques suitable for electron microscopy will be developed for these experiments. It is hoped that the information gained from this model system will lead to a better understanding of lipoprotein metabolism and to the design of more effective measures for the control of lipoprotein disorders in man. Hopefully this will result in the amelioration of the problem of atherosclerosis and of other diseases related to abnormalities of lipoprotein metabolism.