Macrophage lipid efflux and atherosclerosis. The long-term objectives of this project are to gain insight into the mechanism of cholesterol and phospholipid efflux from macrophages to lipid-free apolipoproteins, and the role that this pathway has in preventing atherosclerosis. This project is relevant to atherosclerosis, the most common cause of heart disease, which is the leading cause of death in this country. Reverse cholesterol transport is an antiatherogenic pathway for the removal of cholesterol from the periphery to the liver, where it can be metabolized. HDL and lipid-free apolipoproteins Al and B (apoAl, apoE) are capable of acting as cholesterol acceptors from peripheral cells, and there is overwhelming evidence for a unique mechanism for efflux to apolipoproteins. This efflux pathway is associated with apoAl and apoE binding, uptake, and resecretion, and is defective in subjects with Tangier disease, due to defects in the ABC 1 gene. Macrophages are the earliest cells to accumulate lipid in the developing atherosclerotic lesion, and have been shown to be a crucial cell type in atherogenesis.
The first aim of this project is to use ABC1 transfected cell lines along with morphological and genetic methods to characterize the role of endocytosis and resecretion in this lipid efflux pathway, to determine the cellular location of apoAl lipidation, and to analyze the function of various ABC1 domains by performing site directed mutagenesis and functional studies of the altered ABC1 proteins.
The second aim of this project is to determine the specific role of macrophage ABC 1 in atherosclerosis. This will be determined by the use of mouse models, where ABC 1 will be overexpressed or underexpressed in macrophages in the context of LDL receptor deficiency. These studies will add to our knowledge about the mechanism of reverse cholesterol transport and its antiatherogenic role, and may lead to novel therapeutic strategies to prevent atherosclerosis in humans
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