FATTY ACID EFFECTS ON LIPOPROTEIN BINDING TO RECEPTORS

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Our goal is to determine the effects of dietary saturated and omega-6 polyunsaturated fats (PUFA) on postprandial lipoprotein catabolism via low density lipoprotein (LDL) receptors and the LDL receptor-related protein (LRP). LRP is the putative remnant receptor which Beisiegel et al. recently suggested displayed markedly enhanced lipoprotein binding in the presence of lipoprotein lipase (LPL) (1). In preliminary studies, catabolism of d<1.006 g/ml lipoproteins by LDL receptors on normal human fibroblasts increased after fat feeding, whereas binding of IDL, LDL, and HDL did not change much. Apolipoprotein (apo) E-mediated binding increased as compared to apoB100 binding. Binding of both LDL and d<1.006 g/ml particles to null fibroblasts, which are LDL receptor-negative but express LRP normally, was dramatically increased in the presence of LPL, but catabolism increased only slightly. Furthermore, LDL binding to plastic wells coated with LPL was substantially increased compared to control wells. Taken together, these data suggest that the primary effect of LPL is to enhance binding not the LRP, but to LPL itself, which in turn is anchored to the cell surface by a proteoglycan. More studies are needed to understand the significance of LPL's effects. The proposed studies have the following Specific Aims: Aim 1. Determine if acute fat feeding results in changes in postprandial lipoproteins that increases their catabolism via LDL receptors or (Aim 2) via LRP; Aim 3. Determine if catabolism of postprandial lipoproteins via LDL receptors or LRP is affected by the ratio of dietary omega-6 polyunsaturated to saturated fats whether fed acutely or chronically (28 days); Aim 4. Determine if catabolism of postprandial lipoproteins via LDL receptors and LRP is affected by the presence of apoE isoforms E2, E3, and E4 and by the mass of apoE transferred to d<1.006 g/ml particles from HDL. Normal human subjects with various apoE phenotypes will be fed acute fatty meals on days 21 and 28 of 28-day isocaloric diets containing either a high omega-6 PUFA to saturated (P/S) fat ratio or a low P/S ratio. Thus, both acute and chronic effects of the P/S fat ratio can be determined. Lipoproteins before and after each dietary manipulation will be studied in vitro to determine changes in binding and catabolism of postprandial particles via LDL receptors and LRP. These studies will provide the first detailed information on binding and catabolism of postprandial lipoproteins via LDL receptors and LRP and the role of apoE in this process.