CD36 AND INTESTINAL FAT ABSORPTION

CD36 和肠道脂肪吸收

• 批准号: 7900758
• 负责人: Nada A. Abumrad
• 金额: $ 10万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900758
• 关键词: Acids; Adipocytes; Adipose tissue; Binding; Blood; CD36 gene; Cholesterol; Chylomicrons; Data; Defect; Diabetes Mellitus; Diet; Endoplasmic Reticulum; Enterocytes; Etiology; FABP1 gene; Fasting; Fatty Acids; Fatty acid glycerol esters; Feeds; Functional disorder; Funding; Gastric Inhibitory Polypeptide; Goals; Golgi Apparatus; Grant; Homeostasis; Human; Hyperlipidemia; Insulin Resistance; Intake; Intestines; Knockout Mice; Knowledge; Link; Lipids; Lipoproteins; Lymph; Measures; Membrane Protein Traffic; Membrane Proteins; Metabolic; Molecular; Monoglycerides; Mus; Mutation; Obesity; Outcome; Pancreas; Particle Size; Pathway interactions; Plasma; Play; Predisposition; Process; Production; Proteins; Regulation; Reporting; Resistance; Role; Small Intestines; Testing; Translating; Triglycerides; Very low density lipoprotein; Weight Gain; Work; absorption; apical membrane; base; blood lipid; depressed; feeding; glucose metabolism; human subject; improved; in vivo; insight; insulin secretion; islet; lipid transport; long chain fatty acid; particle; response; trafficking; uptake

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.

描述（由申请人提供）：CD36 是一种多功能膜蛋白，我们于 1993 年鉴定为长链脂肪酸 (FA) 摄取的促进剂。 CD36 的这一作用现已得到我们和其他人获得的大量体内证据的支持。这笔拨款最初是为了研究 CD36 在小肠脂质吸收中的作用，因为它的高表达及其沿胃结肠轴的分布，这与脂质转运中的作用一致。我们的目的是确定 CD36 缺失小鼠的吸收和乳糜微粒产生方面的任何缺陷，并检查对高脂肪饮食诱导的肥胖的易感性。其他研究建议检查 CD36 在引导 FA 产生乳糜微粒中的作用，以及 CD36 和其他涉及 FA 在肠道结合和利用的蛋白质之间可能存在的相互作用。在这笔资助的资助期间，我们证明了 CD36 缺失小鼠肠道的脂质加工缺陷。还发现淋巴中的脂质分泌减少了 50%，原因是乳糜微粒产生缺陷，并且 VLDL 减少更多。我们最近对原代肠细胞的研究表明，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 CD36 缺失小鼠餐后脂蛋白清除率严重受损，这干扰了测量肠道水平 CD36 缺乏的代谢影响的尝试。基于上述内容，本申请提出检验这样的假设：肠细胞顶膜处CD36的存在将脂肪酸靶向甘油三酯形成的单酰甘油途径，从而供给乳糜微粒的产生。更具体地说，我们将检查 CD36 在甘油三酯转移到内质网 (ER) 以及从 ER 转移到高尔基体中的作用。我们的第二个目标是探讨单独靶向肠道中的 CD36 或与靶向 L-FABP 组合是否可以降低餐后血液甘油三酯，从而改善肥胖或糖尿病的预后。我们将通过在 WT 和 L-FABP 无效背景上生成肠道特异性 CD36 缺陷的小鼠来测试这一点。第三，我们最近的数据表明 CD36 在肠促胰岛素释放中的作用，我们将研究这种作用对脂肪摄入和胰岛素分泌的影响。第四，我们建议检查人类 CD36 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 CD36 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分子机制的了解。他们将深入了解肠道 CD36 功能障碍对人类高甘油三酯血症病因的影响。