The overall aim of this project is to use transgenic and gene- inactivated mouse models to determine metabolic pathways leading to the formation of the multiple forms of LDL and IDL found in human plasma. A particular focus is the delineation of the steps involved in the production of small, dense LDL particles. In humans, a predominance of small, dense LDL is associated with changes in triglyceride-rich lipoprotein metabolism, and with increased risk of atherosclerosis. Preliminary evidence from stable isotope kinetic studies in subjects with the small, dense LDL phenotype indicates an increase in rate of production and a reduction in rate of catabolism of large VLDL subspecies (Sf 60-400). These VLDL enter a metabolic cascade that gives rise to smaller VLDL remnant particles and intermediate density lipoproteins (IDL). We hypothesize that a subset of particles in this cascade can be further processed and remodeled to give rise to small, dense LDL. We further hypothesize a critical role for hepatic lipase in this process based on studies in humans, and preliminary evidence from hepatic lipase transgenic rabbits and hepatic lipase knockout mice. These studies will utilize a human apoB transgenic mouse strain that we have shown, in collaboration with Project 0008, to express high levels of multiple human-like LDL subclasses of high fat diets. Lipoproteins isolated from plasma an desolated perfused livers from these mice, as well s from mice with targeted inactivation of the LDL receptor, will be characterized and tested in vivo as potential metabolic precursors of individual ILD and LDL subspecies. Further genetic manipulations will allow testing the role of hepatic lipase and other regulatory proteins, including apoCIII and cholesteryl ester transfer protein, in modulating the distribution of LDL subclasses in vivo, and in particular, in mediating the formation of increased levels of IDL and small, dense LDL that may be of particular importance with regard to atherosclerosis risk. Once the key metabolic determinants of these species have been identified, future studies can be directed at testing their role in generating the atherogenic small, dense LDL phenotype in humans, and at evaluating the influence of other genetic and and environmental influences on its pathologic manifestations. This information, in turn, can be used to develop improved means of diagnosis and management of individuals who are at risk for atherosclerosis as a result of predisposition to this common trait.
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