This application encompasses two Specific Aims. In the first Specific Aim, we will examine macrophage surface binding sites responsible for binding, internalization, and subsequent degradation of the macrophage derived apo E containing particle. In this specific aim, we will test the hypothesis that members of the LDL receptor gene family (LDL receptor, LRP, or VLDL receptor), are responsible for cell surface binding of the macrophage derived - apo E particle. We will also test the hypothesis that proteogylcans are important for cooperating with other cell surface binding sites, and we will examine the internalization and degradation rates mediated by specific cell surface binding sites for the macrophage derived - apo E particle. In the second Specific Aim, we will examine the effect of the macrophage cell surface pool of apo E on the metabolism of exogenous lipoproteins, focusing on two lipoproteins which are metabolized by well defined receptor pathways: LDL and acetylated LDL. We have already shown a difference in the ability of acetylated LDL to load macrophages with cholesterol as a function of macrophage apo E expression. We have also shown that the cell surface pool of apo E modulates binding of apo E free HDL3 to macrophages. In this Specific Aim we will more thoroughly examine the metabolism of LDL and ALDL as it is influenced by the cell surface pool of macrophage derived apo E.
