FATTY ACID EFFECTS ON LIPOPROTEIN BINDING TO RECEPTORS

我们的目标是确定饮食饱和和omega-6的影响 多不饱和脂肪(PUFA)通过低脂对餐后脂蛋白分解代谢的影响 密度脂蛋白受体及其相关蛋白 (LRP)。LRP是Besiegel等人推测的残基受体。 最近提出的显示显著增强的脂蛋白结合在 脂蛋白脂酶(LPL)存在(1)。在初步研究中， 低密度脂蛋白受体对正常人体内1.006 g/ml脂蛋白的分解代谢 脂肪喂养后成纤维细胞增加，而IDL，LDL和 高密度脂蛋白变化不大。载脂蛋白E介导的结合增加 与apoB100结合相比。低密度脂蛋白与低密度脂蛋白的结合；1.006克/毫升 颗粒对成纤维细胞无效，低密度脂蛋白受体阴性但表达 正常情况下，在LPL存在下，LRP显著增加，但 分解代谢仅略有增加。此外，低密度脂蛋白与塑料的结合 与对照相比，涂有LPL的Wells显著增加 威尔斯。综上所述，这些数据表明，LPL的主要作用 不是增强LRP的绑定，而是增强与LPL本身的绑定，而LPL本身又是 由一种蛋白多糖固定在细胞表面。需要更多的研究来 理解LPL的影响的意义。拟议的研究包括 以下具体目标：目标1.确定急性脂肪喂养的结果 餐后脂蛋白的变化通过增加其分解代谢 低密度脂蛋白受体或(目标2)通过LRP；目标3。确定是否分解代谢 通过低密度脂蛋白受体或LRP的餐后脂蛋白受该比率的影响 膳食中omega-6多不饱和脂肪到饱和脂肪的比例，无论是急性喂养还是 慢性(28天)；目标4.确定餐后分解代谢 载脂蛋白E通过低密度脂蛋白受体和LRP影响脂蛋白 E_2、E_3和E_4的异构体以及通过转移到d&lt；1.006 g/ml的载脂蛋白E的质量 来自高密度脂蛋白的颗粒。具有不同载脂蛋白E表型的正常人 将在28天等卡路里饮食的第21天和第28天喂食急性高脂膳食 含有高omega-6多不饱和脂肪酸与饱和(P/S)脂肪比率或低 P/S比值。因此，P/S脂肪比例的急性和慢性影响都可以 要下定决心。每次饮食操作前后的脂蛋白 将在体外进行研究，以确定结合和分解代谢的变化 餐后颗粒通过低密度脂蛋白受体和LRP。这些研究将 提供有关结合和分解代谢的第一个详细信息 低密度脂蛋白受体和LRP介导的餐后脂蛋白及载脂蛋白E在糖尿病中的作用 这一过程。

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.