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，我们在1993年确定为长链脂肪酸（FA）摄取的促进剂。 CD36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。该赠款最初是为了检查CD36在小肠中的脂质吸收中的作用，该作用基于其高表达及其沿胃colonic轴的分布，这与在脂质转运中的作用一致。我们的目的是定义CD36无效小鼠吸收和乳糜微粒产生的任何缺陷，并检查对高脂饮食诱导的肥胖症的敏感性。其他研究提出的研究旨在检查CD36在将FA引导到乳糜微粒产生的作用，以及CD36与与FA结合和利用肠道中有关的CD36与其他蛋白质之间的可能相互作用。在这笔赠款的资助期间，我们证明了CD36 Null小鼠的肠道中的脂质加工缺陷。还发现YMPH中脂质的分泌因乳糜微粒产生缺陷而降低50％，并转移到更多的VLDL降低。我们最近使用原发性肠细胞的工作表明，分泌缺陷是近端肠中FA和胆固醇摄取的Mpairments造成的。最后，我们已经记录了CD36 NULL小鼠中餐后脂蛋白的严重清除，该清除涉及测量CD36缺乏症在肠道水平上的代谢影响的尝试。基于上述目前的应用，提出了以下假设：肠肠细胞顶膜上CD36的存在将脂肪酸靶向甘油三酸酯形成的单酰甘油途径，从而供胆小性甘油三酸酯形成。更具体地说，我们将研究CD36在甘油三酸酯转移到内质网（ER）以及从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结合的肠中CD36是否可以降低餐后血液甘油三酸酯以改善肥胖或糖尿病的预后。我们将通过在WT和L-FABP NULL背景上生成具有CD36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CD36在肠肠降低剂的释放中的作用，我们将研究该作用在脂肪摄入和胰岛素分泌方面的含义。第四我们建议检查CD36缺乏症对人类脂质吸收的代谢影响，餐后脂蛋白的清除和肠降低蛋白释放。据报道，人类的CD36缺乏与餐后和禁食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降低蛋白释放的分子机制的了解。他们将洞悉肠CD36中功能障碍对人类高甘油血症病因的贡献。