CD36 and Intestinal Fat Absorption

血小板颗粒摘要：CD 36和肠脂肪吸收（R 01 DK 060022） CD 36或清道夫受体B2在进化过程中高度保守，具有代谢和免疫调节作用。 功能协调发展的我们的研究结果共同表明，CD 36在肠道中有五个主要功能：1）FA的吸收， 近端肠，2）乳糜微粒合成和乳糜微粒输入淋巴的启动，3） 对肠道病原体的完全免疫应答，4）促进中性粒细胞清除和5）细胞外基质 (ECM)修复和重建[40]。根据我们最近的研究结果，我们提出，低或功能障碍， 肠道CD 36可能是膳食脂肪诱导的肠道炎症的易感基因。我们的假设是 ECM重塑将诱导肠道炎症，并且与受损的免疫细胞功能一起将导致 肠道炎症进展至全身水平，涉及多个器官，并发展为全身 胰岛素抵抗事实上，亚临床炎症似乎存在于携带次要等位基因的肥胖受试者中 一个能降低50%的CD 36水平的编码SNP。我们在目标1中提出的研究将检查CD 36在以下方面的作用： 膳食脂肪诱导的ECM重塑和肠道免疫力的改变，并将产生相关的信息， 肥胖症的主要并发症的病因。我们还将对CD 36受试者进行免疫细胞分析， 缺陷肠道影响全身内稳态的另一种方式是通过肠道分泌物， 吸收前期这一阶段对人体的最佳营养加工和能量代谢非常重要。 然而，人们对它的调节以及为什么它在2型糖尿病中变钝知之甚少。我们的初步数据 表明部分CD 36缺乏个体的吸收前分泌物钝化。我们在目标2中建议， 研究CD 36-/-小鼠中吸收前期的组分，并确定其是否由CD 36介导 使用通过在神经节前细胞中缺失CD 36产生的新小鼠， 使用Phox 2b-Cre的副交感神经元。在目标3中，我们将研究CD 36在胃中的作用。 CD 36在胃中的表达是小鼠中最高的（数据未显示），尽管它在胃中的表达是最高的。 在2001年证实的CD 36在胃中的任何作用尚未被研究。我们的初步数据显示 CD 36在胃的内皮细胞（EC）和壁细胞（PC）上高度表达，并且CD 36缺失 改变PC形态和功能。我们将研究EC或PC中的CD 36缺失如何影响PC代谢 和功能以及对ECM重塑的影响和对高脂饮食、高他莫昔芬损伤的反应 治疗或幽门螺杆菌感染。总的来说，目标1-3中的研究将增加我们对肠道的理解。 体内平衡功能，它们如何被过量的膳食脂肪改变以及相关的全身影响。 所获得的信息可以帮助设计新的治疗方法，以减轻肠道炎症及其 系统性影响。

ABSTRACT OF PARENT GRANT: CD36 and Intestinal Fat Absorption (R01 DK060022) CD36, or scavenger receptor B2, is highly conserved through evolution and has metabolic and immune functions. Our findings together suggest that CD36 has five major functions in the gut: 1) FA uptake by the proximal intestine, 2) initiation of chylomicron synthesis and chylomicron input into the lymph, 3) mounting of a full immune response to enteric pathogens, 4) facilitating neutrophil clearance and 5) extracellular matrix (ECM) remodeling and tissue repair [40]. Based on our recent findings we propose that low or dysfunctional gut CD36 can be a susceptibility gene for dietary fat induced gut inflammation. Our hypothesis is that abnormal ECM remodeling will induce gut inflammation and together with impaired immune cell function will lead to progression of gut inflammation to the systemic level involving multiple organs with development of whole body insulin resistance. Indeed, subclinical inflammation appears present in obese subjects carrying the minor allele of a coding SNP that reduces CD36 level by 50%. The studies we propose in aim 1 will examine CD36’s role in dietary fat induced alterations of ECM remodeling and immunity in the gut and will yield information relevant to etiology of major complications of obesity. We will also conduct immune cell profiling of subjects with CD36 deficiency. Another way by which the gut influences systemic homeostasis is through secretions of the preabsorptive phase. This phase in people is important for optimal nutrient processing and energy metabolism. However, little is known about its regulation and why it is blunted in type-2 diabetes. Our preliminary data indicate blunting of preabsorptive secretions in individuals with partial CD36 deficiency. We propose in aim 2 to study the components of the preabsorptive phase in CD36-/- mice and to determine if it is mediated by CD36 expression on vagal neurons using a new mouse generated by deletion of CD36 in preganglionic parasympathetic neurons using the Phox2b-Cre. In aim 3 we will study the role of CD36 in the stomach. Expression of CD36 in the stomach is among the highest in the mouse (data not shown) and although it was demonstrated in 2001 any role of CD36 in the stomach has not been examined. Our preliminary data indicate CD36 is highly expressed on endothelial cells (EC) and parietal cells (PC) in the stomach and CD36 deletion alters PC morphology and function. We will examine how CD36 deletion in EC or PC impacts PC metabolism and function and the impact on ECM remodeling and response to injury from high fat diet, high tamoxifen treatment or H pylori infection. Overall the studies in aims 1-3 are will increase our understanding of gut homeostatic functions, how they are altered by excess dietary fat and the associated systemic implications. The information obtained could help design novel therapeutic approaches to alleviate gut inflammation and its systemic impact.