Lipids and lipoproteins play an important role in the development of atherosclerotic cardiovascular disease. The structure, function, and metabolism of lipoproteins have been intensively investigated utilizing both in vivo and in vitro experimental methods. One of the most productive techniques utilized for the investigation of the function and metabolism of the proteins associated with lipoprotein particles, the apolipoproteins, has been in vivo kinetic studies. ? ? The maturation of high-density lipoprotein (HDL) is important for reverse cholesterol transport, a hypothesis that HDL transports cholesteryl ester (CE) from peripheral atherosclerotic lesions to the liver. This hypothesis is based on epidemiological studies that indicated an inverse correlation between the HDL cholesterol (HDL-C) levels and the prevalence of coronary heart disease (CHD) as an independent anti-atherogenic factor for CHD. It is therefore interesting to note that despite a markedly low level of HDL-C some people dont develop CHD while others with extremely high HDL can develop CHD. Little is known about the initiation of this process in humans? ? Our aim was to elucidate the mechanism(s) responsible for the formation and maturation of HDL using in vitro cell cultures, animal models and correlating this in vivo in humans who are normal and have genetic mutations in specific lipid pathways. Studies are designed to formulate metabolic pathways in patients with defined genetic disorders of lipid metabolism as well as in healthy volunteers to provide new and novel insights into normal and pathologic metabolic pathways. All kinetic data is computer analyzed to provide quantitative data and facilitate direct comparison of multiple studies.? ? The metabolism of very low density lipoproteins (VLDL), low density lipoproteins (LDL), high density lipoproteins (HDL), and their associated apolipoproteins has been studied in vitro in cells, in animal models lacking genes (KO mice) or overexpressing genes (transgenic) and in normal and dyslipoproteinemic subjects. Our early studies have laid the foundation for the understanding of many of the key metabolic pathways in lipid metabolism. It is well accepted that VLDL serves as a precursor for LDL, and during this conversion triglycerides and the apolipoprotein C peptides are selectively removed. It has also been shown that the major defect in type II hyperlipoproteinemia appears to be decreased LDL catabolism. We have shown that HDL concentrations are influenced by the apolipoprotein composition of the HDL particles. HDL particles containing only apolipoprotein A-I (LpA-I) are catabolized differently than HDL particles containing both apolipoprotein A-I and A-II (LpA-I:AII). Studying the effects of diet, drug, and genetic factors upon these different particles has permitted a better understanding of what modulates HDL levels.
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