CD36 AND INTESTINAL FAT ABSORPTION

CD 36是我们在1993年发现的一种多功能膜蛋白，作为长链脂肪酸（FA）的促进剂。 摄取。CD 36的这种作用现在得到了我们和其他人获得的大量体内证据的支持。 这项资助最初是为了研究CD 36在小肠脂质吸收中的作用， 其高表达及其沿胃-结肠轴的沿着分布，这与在胃-结肠轴中的作用一致。 脂质转运我们的目的是确定在CD 36 null中吸收和乳糜微粒产生的任何缺陷， 小鼠，并检查对高脂肪饮食诱导的肥胖症的易感性。其他研究建议审查 CD 36在引导FA产生乳糜微粒中的作用以及CD 36与 其他蛋白质涉及FA结合和利用在肠道中。在这笔资金的资助下，我们 证实了CD 36敲除小鼠肠的脂质加工缺陷。脂肪的分泌 淋巴也被发现有50%的下降，乳糜微粒产生缺陷和转移到更多的VLDL 还原我们最近对原代肠上皮细胞的研究表明，分泌缺陷是由于 近端肠中FA和胆固醇摄取的损害。最后，我们记录了严重的 在CD 36缺失小鼠中，餐后脂蛋白的清除率降低，这干扰了 在肠道水平测量CD 36缺乏对代谢的影响。基于以上所述， 本申请提出检验以下假设：在肠上皮细胞顶端存在CD 36 膜靶向脂肪酸的甘油三酸酯形成的单酰基甘油途径，饲料 乳糜微粒产生。更具体地说，我们将研究CD 36在甘油三酯转移到细胞中的作用。 内质网（ER）和从ER到高尔基体。我们的第二个目标是探索 肠道中的CD 36，单独或与靶向L-FABP组合，可以降低餐后血液 甘油三酯用于改善肥胖症或糖尿病的结果。我们将通过生成一个具有 WT和L-FABP无效背景下的CD 36的精氨酸特异性缺陷。第三，我们最近的数据表明， CD 36在肠肠促胰岛素释放中的作用，我们将研究这种作用的意义， 脂肪摄入量和胰岛素分泌。第四，我们建议检查CD 36的代谢影响。 人体中脂质吸收、餐后脂蛋白和肠促胰岛素清除方面的缺陷 release.据报道，人类中的CD 36缺乏与血脂异常有关， 餐后和禁食状态。这些研究将扩大我们对分子生物学的认识， 乳糜微粒形成和肠促胰岛素释放的潜在机制。他们将深入了解 肠CD 36功能障碍对人类高甘油三酯血症病因学的贡献。

CD36 is a multifunctional membrane protein we identified in 1993 as a facilitator of long-chain fatty acid (FA) uptake. This role of CD36 is now supported by a wealth of in vivo evidence obtained by us and by others. This grant was initially submitted to examine the role of CD36 in lipid absorption in the small intestine, based on its high expression and its distribution along the gastro-colonic axis, which are consistent with a role in lipid transport. Our aims were to define any defects in absorption and chylomicron production in CD36 null mice and to examine susceptibility to high fat diet-induced obesity. Other studies proposed to examine the role of CD36 in directing the FA to chylomicron production and possible interactions between CD36 and other proteins implicated in FA binding and utilization in the intestine. During the funding of this grant we demonstrated a defect in lipid processing by the intestine of the CD36 null mouse. Secretion of lipid in the ymph was also found to be 50% depressed with a defect in chylomicron production and a shift to more VLDL reduction. Our recent work with primary enterocytes indicates that the defect in secretion is consequent to mpairments in FA and cholesterol uptake in the proximal intestine. Finally, we have documented severely mpaired clearance of postprandial lipoproteins in the CD36 null mouse which interferes with attempts to measure the metabolic impact of CD36 deficiency at the level of the intestine. Based on the above the current application proposes to examine the hypothesis that the presence of CD36 at the enterocyte apical membrane targets the fatty acid to the monoacylglycerol pathway of triglyceride formation that feeds chylomicron production. More specifically we will examine the role of CD36 in transfer of triglycerides to the endoplasmic reticulum (ER) and from the ER to the Golgi. Our second goal is to explore whether targeting CD36 in the intestine, alone or in combination with targeting L-FABP, can lower postprandial blood triglycerides for improving outcome in obesity or diabetes. We will test this by generating a mouse with intestine-specific deficiency of CD36 on the WT and L-FABP null backgrounds. Third our recent data indicate a role of CD36 in the release of intestinal incretins and we will examine the implications of this role with respect to fat intake and insulin secretion. Fourth we propose to examine the metabolic impact of CD36 deficiency in humans with respect to lipid absorption, clearance of postprandial lipoproteins and incretin release. CD36 deficiency in humans has been reported to be associated with abnormalities of blood lipids in both the postprandial and fasted states. The studies will expand our knowledge of the molecular mechanisms underlying chylomicron formation and incretin release. They will provide insight into the contribution of dysfunctions in intestinal CD36 to the etiology of hypertriglyceredemia in humans.