Enhanced Hepatic Lipoprotein Uptake and Atherogenesis

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DESCRIPTION (provided by applicant): Lowering plasma cholesterol lowers the risk of coronary heart disease. A general approach to lowering plasma cholesterol is to increase receptors that accelerate the catabolism of the atherogenic lipoproteins (Lps) througi iepatic uptake. We propose an alternative method to increase the catabolism of apo B-containing Lps; that is, adding a small peptide to the circulation that binds to the Lp surface and ensures its rapid, targeted delivery to the liver for removal from circulation and away from the periphery. To accomplish this, we have designed peptide mimetics that contain a highly efficient phospholipid-binding domain and attached this lipoprotein targeting domain to an Arg-rich domain of apo E that allows putative interaction with receptors and cell-surface proteoglycans. Preliminary data presented here indicate that one such peptide indeed has these properties and dramatically reduce plasma total cholesterol (TC) levels in the apo E (-/-) mouse model of atherosclerosis, independent of the route o peptide delivery. In addition, this peptide lowered TC dramatically and rapidly in two other mouse models, the apo E(-/)//LDL-R(-/-) and the cholesterol-fed C57BL/6 mouse. This alternative method for lowering plasma TC might be most efficacious in subjects with receptor-defective dyslipidemias. To further develop and understand these phenomena we propose two specific aims. la) To characterize the minimum structural requirements of these peptides that control Lp binding and hepatic removal of atherogenic lipoproteins, b) to determine the molecular mechanisms of peptide-mediated binding and uptake of atherogenic Lps using receptor-defective and proteoglycan-deficient cell lines as well as hepatocytes from atherosclerosis mouse models. 2). To determine the in viw metabolism of the peptide-mediated removal of atherogenic lipoproteins in murine models of atherosclerosis. The data generated will provide the molecular basis and understanding for the use of needed alternative strategies o lowering high plasma cholesterol levels. It will also provide a rational basis for the design and delivery of peptide mimetics and for their therapeutic use in the treatment of atherosclerosis.