Peter Barrett, Ph.D. - US grants

The overall goal of the proposed research is to characterize the kinetics of the potentially atherogenic lipoproteins, low density lipoprotein (LDL), in normolipidemic individuals. In hyperlipidemic subjects, an association exists between risk for coronary artery disease (CAD) and a preponderance of small, dense LDL particles, known as atherogenic lipoprotein phenotype B (ALP-B). It has been suggested that the presence of a single gene accounts for this phenotype and the associated elevated levels of triglyceride. In normolipidemic subjects, ALP-B is also associated with increased plasma triglyceride and reduced HDL cholesterol levels. Because the frequency of this gene is the same in normolipidemic and hyperlipidemic subjects, normolipidemic subjects with the ALP-B may also be at increased risk for CAD. Because of the significance of LDL, and its role in the development of CAD, the studies described in this proposal will examine the kinetics of LDL particles in normolipidemic subjects. The hypotheses to be tested are that among subjects with a predominance of small, dense LDL, the size and density distribution of LDL particles are due to: (a) increased production of small, dense LDL particles, and/or (b) decreased catabolism of these particles. Apolipoprotein B (apoB) turnover studies will be performed to test these hypotheses. These studies will use three isotopes (125I, 131I, and 3H- leucine) which will be introduced exogenously and endogenously to trace the appearance and disappearance of apoB into and from the LDL fraction. Multicompartmental models will be developed to analyze the tracer data. Many studies have focused on the metabolism of lipoproteins in hyperlipidemic subjects and have described the heterogeneous nature of all classes of lipoprotein particles. Few metabolic studies however have examined lipoprotein heterogeneity within the normolipidemic population. Although it is accepted that lipoproteins in normolipidemics are heterogeneous, there was little interest in this observation until recently. As in hyperlipidemic individuals, normolipidemic individuals may also be at increased risk for CAD because of the heterogeneity within the LDL fraction. These studies therefore propose to investigate lipoprotein heterogeneity within the LDL fraction by conducting and analyzing a series of lipoprotein turnover studies.

The goals for this fellowship are to develop and test the application of compartmental models to describe lipoprotein tracer data. This fellowship will focus on two problems. The first being the development of a compartmental model to describe the kinetics of apolipoprotein B (apoB) and triglyceride within the VLDL, IDL and LDL fractions of individuals with visceral obesity on eicosapentanoic acid and Atorvastatin (an HMGCoA reductase inhibitor) therapy. The novelty of this study involves the simultaneous use of tracers for the apoB and triglyceride moieties of the lipoprotein particles. The second problem will involve the development and testing of a compartmental model of chylomicron remnant metabolism using a breath test. Previous studies have used the Vitamin A protocol, the results of which are difficult to analyze. The goal of this project is to develop a model which will describe the rates of remnant catabolism following the infusion of labeled fatty acids.