This Center will continue to focus its efforts on the metabolism of lipids and lipoproteins in relation to atherogenesis. The biology of the macrophage is under investigation from several points of view: chemotaxis and its mechanisms; receptor mediated lipoprotein uptake, particularly by way of the acetyl LDL receptor; the role of secreted lipoprotein lipase; mechanisms involved in mobilization of stored lipids; factors that may regulate lipid-mobilizing enzymes; uptake by the macrophage of denatured proteins. Particular emphasis will be placed on the endothelial cell-modification of LDL that results in enhanced macrophage degradation of it, exploring the interrelationships among the oxidative changes in the LDL, the phospholipase A2 activity that appears to be involved and the changes in apoprotein B100. Parallel with these studies we propose to extend our studies on lipoprotein degradation by arterial tissue in vivo, carried out initially using tyramine cellobiose-labeled LDL, extending those studies to include other lipoproteins that may be involved in atherogenesis, especially beta-VLDL. The implications of post-translational modification of lipoprotein structure continues to be a major theme. The implications of glucosylated LDL have been previously discussed; several other post-translational modifications recently described will be studied as to their possible role in autoimmune diseases. The biosynthesis and secretion of lipoproteins by cultured hepatocytes is under study, attempting to reconstruct the sequence of events involved using immunoelectron microscopy. The mechanisms by which HDL delivers cholesterol esters to the liver and adrenal is under continued exploration, emphasizing molecular mechanisms involved. At the clinical level, the intriguing alterations in circulating LDL induced by cholestyramine treatment is under further study and its implications with regard to LDL heterogeneity are being explored. Studies on the mechanism of action of probucol, recently shown in this laboratory to involve alterations in LDL-cell interaction, will be extended to studies in man. Finally, the clinical effectiveness of mevinolin in the treatment of hypercholesterolemia will be studied and, in particular, the use of mevinolin in combination with probucol.
