CD36 AND INTESTINAL FAT ABSORPTION

摘要 CD 36或清道夫受体B2在进化过程中高度保守，具有代谢和免疫功能。 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的近端摄取， 肠，2）启动乳糜微粒合成和乳糜微粒输入淋巴，3）安装完全免疫 对肠道病原体的反应，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]。基于我们最近的研究结果，我们提出低或功能失调的肠道CD 36可能是一个重要的因素。 膳食脂肪诱导肠道炎症易感基因。我们的假设是异常的ECM重塑 将诱导肠道炎症，并与受损的免疫细胞功能一起导致肠道疾病的进展 全身性炎症涉及多个器官，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编码SNP的次要等位基因的肥胖受试者中 降低50%的CD 36水平。我们在目标1中提出的研究将检查CD 36在膳食脂肪诱导的 ECM重塑和肠道免疫的改变，并将产生与主要疾病的病因学相关的信息。 肥胖的并发症。我们还将对CD 36缺乏症受试者进行免疫细胞分析。另一 肠道影响全身内稳态的方式是通过吸收前阶段的分泌物。这 人的生长阶段对于最佳的营养加工和能量代谢很重要。然而， 关于它的调节以及为什么它在2型糖尿病中变钝。我们的初步数据显示 部分CD 36缺乏的个体中的吸收前分泌物。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表达介导 使用通过在节前副交感神经元中缺失CD 36产生的新小鼠对迷走神经元的作用 使用Phox 2b-Cre。在目标3中，我们将研究CD 36在胃中的作用。CD 36在乳腺癌中的表达 胃是小鼠中最高的（数据未显示），尽管它在2001年被证明任何作用， CD 36在胃中的分布还没有被研究过。我们的初步数据表明，CD 36高表达于 内皮细胞（EC）和壁细胞（PC）在胃和CD 36缺失改变PC形态， 功能我们将研究EC或PC中的CD 36缺失如何影响PC的代谢和功能， ECM重塑和对高脂饮食、高他莫昔芬治疗或幽门螺杆菌感染损伤的反应。 总的来说，目标1-3中的研究将增加我们对肠道稳态功能的理解， 被过量的膳食脂肪和相关的全身影响所改变。所获得的信息可能有助于 设计新的治疗方法，以减轻肠道炎症及其全身影响。

ABSTRACT 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.