CD36 AND INTESTINAL FAT ABSORPTION

描述（由申请人提供）：CD 36是一种多功能膜蛋白，我们在1993年鉴定为长链脂肪酸（FA）摄取的促进剂。我们和其他人获得的大量体内证据支持CD 36的这种作用。该基金最初提交的目的是研究CD 36在小肠脂质吸收中的作用，其基础是CD 36的高表达及其沿着胃-结肠轴的分布，这与脂质转运中的作用一致。我们的目的是确定任何缺陷的吸收和乳糜微粒生产的CD 36裸小鼠和检查易感性高脂肪饮食诱导的肥胖。其他研究建议检查CD 36在引导FA产生乳糜微粒中的作用，以及CD 36与其他涉及FA结合和肠道利用的蛋白质之间可能的相互作用。在资助该基金期间，我们证明了CD 36缺失小鼠肠道的脂质加工缺陷。淋巴液中的脂质分泌也被发现有50%的抑制，乳糜微粒产生缺陷，并转向更多的VLDL减少。我们最近对原代肠上皮细胞的研究表明，分泌缺陷是近端肠中FA和胆固醇摄取受损的结果。最后，我们记录了严重受损的清除餐后脂蛋白在CD 36 null小鼠，干扰试图测量的代谢影响的CD 36缺乏症在肠道的水平。基于上述内容，本申请提出检查肠上皮细胞顶端膜处存在的CD 36将脂肪酸靶向于供给乳糜微粒产生的甘油三酯形成的单酰基甘油途径的假设。更具体地说，我们将研究CD 36在甘油三酯转移到内质网（ER）和从ER到高尔基体中的作用。我们的第二个目标是探索单独或与靶向L-FABP组合靶向肠道中的CD 36是否可以降低餐后血液甘油三酯以改善肥胖或糖尿病的结局。我们将通过在WT和L-FABP无效背景下产生具有CD 36的精氨酸特异性缺陷的小鼠来测试这一点。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与脂肪摄入和胰岛素分泌的关系。第四，我们建议研究人类CD 36缺乏对脂质吸收、餐后脂蛋白清除和肠促胰岛素释放的代谢影响。据报道，人类的CD 36缺乏与餐后和空腹状态下的血脂异常有关。这些研究将扩大我们对乳糜微粒形成和肠促胰岛素释放的分子机制的认识。他们将提供深入了解肠道CD 36功能障碍对人类高甘油三酯血症病因学的贡献。

DESCRIPTION (provided by applicant): 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.