CD36 and Intestinal Fat Absorption

家长资助摘要：CD36与肠道脂肪吸收(R01 DK060022) CD36，或清道夫受体B2，在进化过程中高度保守，具有代谢和免疫功能 功能。我们的发现表明，CD36在肠道中有五个主要功能：1)肠道对FA的吸收 近端肠，2)启动乳胶粒合成并将乳胶粒输入淋巴，3)安装 对肠道病原体的全面免疫反应，4)促进中性粒细胞清除和5)细胞外基质 (ECM)重塑和组织修复[40]。根据我们最近的发现，我们认为低血压或功能失调 肠道CD36可能是膳食脂肪引起肠道炎症的易感基因。我们的假设是不正常的 细胞外基质重塑会导致肠道炎症，并与免疫细胞功能受损一起导致 随着全身发育，肠炎向全身多器官水平发展 胰岛素抵抗。事实上，携带轻微等位基因的肥胖受试者似乎存在亚临床炎症。 将CD36水平降低50%的编码SNP。我们在目标1中提出的研究将考察CD36的S在 膳食脂肪诱导肠道细胞外基质重塑和免疫功能的改变，并将提供与 肥胖症主要并发症的病因学。我们还将对CD36携带者进行免疫细胞图谱分析 缺乏症。肠道影响全身动态平衡的另一种方式是通过分泌 吸收前期。人体的这一阶段对于最佳营养处理和能量新陈代谢非常重要。 然而，人们对它的调控以及为什么它在2型糖尿病中变得迟钝知之甚少。我们的初步数据 提示CD36部分缺乏者吸收前期分泌物变钝。我们在目标2中建议 研究CD36-/-小鼠吸收前期的成分并确定其是否由CD36介导 节前CD36缺失小鼠迷走神经细胞的表达 使用PHOX2B-CRE的副交感神经元。在目标3中，我们将研究CD36在胃中的作用。 CD36在小鼠胃中的表达是最高的之一(数据未显示)，尽管它是 2001年证明，CD36在胃中的任何作用都没有被研究过。我们的初步数据显示 CD36在胃内皮细胞(EC)和壁细胞(PC)上高表达，CD36缺失 改变PC的形态和功能。我们将研究EC或PC中CD36缺失对PC新陈代谢的影响 高脂饮食、高三苯氧胺对细胞外基质重塑和损伤反应的影响 治疗或幽门螺杆菌感染。总体而言，目标1-3中的研究将增加我们对Gut的理解 动态平衡功能，它们是如何被过量的饮食脂肪改变的，以及相关的全身影响。 所获得的信息可能有助于设计新的治疗方法来缓解肠道炎症和 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.