Studies on the Structural and Metabolic Heterogeneity in Low Density Lipoprotein

This thesis sought to investigate the relationship between structural and metabolic heterogeneity in LDL and examine the influence of plasma triglyceride on the properties of this lipoprotein. A technique to quantify individual LDL subfractions was developed which was superior to previously published methods and was employed to characterise three LDL subfractions in normals and in subjects with coronary disease, primary hyperlipidaemia and the secondary hyperlipidaemia observed in non insulin dependent diabetes mellitus and the nephrotic syndrome. In a case controlled study, a sevenfold increased risk of myocardial infarction was found to be associated with a concentration of small dense LDL III > 100mg/100ml. Subjects with hypertriglyceridaemia, combined hyperlipidaemia and the secondary hyperlipidaemia were found to exhibit an atherogenic lipoprotein phenotype of raised plasma triglyceride, low HDL cholesterol and a preponderance of small dense LDL. The data in the entire cohort was pooled and multivariate analysis revealed that plasma triglyceride was the most important independent predictor of LDL III. Pharmacological modulation of the LDL profile was investigated in normals and in a variety of hyperlipidaemic states using the main classes of lipid lowering drugs- resins, nicotinic acid derivatives, fibrates and statins. Those drugs which act through the lowering of plasma triglyceride reduced the concentrations of LDL III and those whose mode of action is by activation of the LDL receptor, reduced the concentrations of the larger LDL I and LDL II species. An important finding was in the unexpected beneficial effect of statins in combined hyperlipidaemia when LDL III concentrations were lower than expected for the plasma triglyceride level. Kinetic heterogeneity of LDL was studied by undertaking radioactive turnovers in normals and hypercholesterolaemic subjects who were given triglyceride lowering therapy. A two pool model for plasma LDL was developed to explain the radioactive decay curves of plasma and urine. One pool (pool A) was rapidly removed by the LDL receptor while the other (pool B) was more slowly removed and its synthesis was positively related to plasma triglyceride. The kinetics of apo-LDL were further examined in subjects with moderate hypertriglyceridaemia. Here it was necessary to expand the model to a third plasma pool (pool C) to account for an LDL species which was rapidly catabolised by receptor- independent mechanisms. A high level of receptor-independent catabolism was associated with an increased ratio of LDL III to LDL II. Pool C was seen in subjects with plasma triglyceride >2.5mmol/l in whom there was the presence of an abnormally small, dense LDL. On the basis of these observations and published VLDL metabolic studies, a model was postulated in which pool A LDL was produced from the delipidation of hepatic lipoproteins secreted in the Sf 0-60 density range and circulated m the form LDL I and LDL II. Pool B LDL, on the other hand, was derived from large triglyceride-rich VLDL of Sf 60-400 and circulates in most subjects in the form of LDL II. Neutral lipid exchange and lipolysis via the agency of hepatic lipase converts a proportion of pool B LDL II to LDL III, depending on the level of plasma triglyceride and the activity of the lipase enzyme. The data presented in this thesis are in line with current concepts of the atherogenicity of small dense LDL and provide evidence that it is an independent risk factor for coronary disease. It demonstrates that the properties of LDL are strongly influenced by its pedigree. Furthermore it shows that there are currently available drugs that are capable of altering not only the quantity of LDL but also its quality and offer hope in the continuing problem of tackling coronary heart disease