Role of mesenteric lymphatics and dietary endotoxin in metabolic syndrome

肠系膜淋巴管和膳食内毒素在代谢综合征中的作用

• 批准号: 8803103
• 负责人: MARIAPPAN MUTHUCHAMY
• 金额: $ 10万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803103
• 关键词: ADD-1 protein; Address; Adipose tissue; Affect; Animal Model; Animals; Blood; Body Fluids; Calcium; Cardiovascular Diseases; Cells; Central obesity; Characteristics; Chronic; Chylomicrons; Cues; Cyclic GMP; Data; Development; Diagnostic; Diet; Dietary Fats; Disease Progression; Dyslipidemias; Endotoxins; Enzyme-Linked Immunosorbent Assay; Exhibits; Fatty Liver; Fatty acid glycerol esters; Fructose; Functional disorder; Health; Homeostasis; Hypertension; IL8 gene; Immune; Immune system; Immunofluorescence Immunologic; Immunohistochemistry; In Situ; Inflammation; Inflammatory; Interleukin-13; Interleukin-4; Interleukin-5; Interleukins; Intestines; Lead; Length; Lipids; Lipopolysaccharides; Liver diseases; Lymph; Lymphatic; Lymphatic System; Lymphatic vessel; MAP Kinase Gene; MAPK14 gene; Measurement; Measures; Mediating; Mesentery; Metabolic; Metabolic syndrome; Metabolism; MicroRNAs; Modeling; Molecular; Muscle Cells; Neuromodulator; Non-Insulin-Dependent Diabetes Mellitus; Pathologic; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phosphorylation; Physiological; Play; Preparation; Production; Publishing; Rattus; Recruitment Activity; Regulation; Risk; Role; Route; Small Intestines; Structure; Substance P; Testing; Tissues; Tumor Necrosis Factor-alpha; absorption; atherogenesis; base; cell type; chemokine; cytokine; eosinophil; fasting glucose; genetic regulatory protein; improved; in vivo; lipid metabolism; lymph flow; lymphatic pump; macrophage; neutrophil; peptide hormone; pressure; public health relevance; research study; tool; trafficking

DESCRIPTION (provided by applicant): Although more than 95% of dietary lipids are absorbed from the small intestine via the intestinal lymphatics, transported via the mesenteric collecting lymphatics through the lymphatic network en route to the blood, the role of lymph transport in the regulation of lipid metabolism is poorly understood. We have recently shown that high fructose diet-induced metabolic syndrome (MetSyn) rats exhibit impaired mesenteric lymphatic function. Dietary endotoxin readily associates with chylomicrons and are primarily absorbed through the mesenteric lymphatics along with many other gut peptides and hormones, suggesting that the primary trafficking of dietary endotoxins, such as, lipopolysaccharide (LPS) is via lymphatics. Hence, important questions remain unanswered: 1) what are the roles of lymphatic function in and responsiveness to dietary endotoxin and 2) how does that affect the progression of MetSyn. Our preliminary data show that immune cells, eosinophils and neutrophils are present on or adjacent to the lymphatic wall, and that the number of these immune cells on the lymphatic wall is decreased in LPS-induced inflamed mesenteric tissue. These data provide the basis for our central hypothesis: That dietary endotoxins alters the local cues (major cytokines of eosinophil and neutrophil: IL-4, IL-5, IL-8 and IL-13) in the mesenteric milieu that impairs lymphatic function and chylomicron transport, which leads to dyslipidemia and mesenteric adipose accumulation, both key pathologic determinants of the development of MetSyn. We will use the high-fructose and high-fat diet-induced MetSyn rat models and a LPS-induced inflammation model to determine the roles of the lymphatic system in the pathophysiology of MetSyn. Specific Aims are: 1) To demonstrate the linkages between dietary endotoxins, pro-inflammatory cytokines and lymphatic function during the development of MetSyn; 2) To determine the functional consequences and molecular mechanisms of reduced lymph transport in the development of MetSyn; and 3) To test the roles of micro RNAs (miRs) that interconnect the regulation of IL-8, IL-4, IL-5 and IL-13 in modulating lymphatic function during the development of MetSyn. We will use whole-mount mesenteric preparations for immunohistochemical studies, in situ preparations for lymph flow and lymphatic contractility, isolated/cannulated vessels for contractile characteristics of lymphatics, wire-myograph studies for length- tension and force-calcium measurements. These experiments will specifically address how dietary endotoxins effect the M1 and M2 macrophage polarization on lymphatics and the mechanisms by which the eosinophil and neutrophil interleukins, IL-4, IL-5, IL-8 and IL-13, and miR-19a, 93, 200c and 203 in lymphatic muscle cells regulate the lymphatic structure and function. Thus, this proposal will identify important targets bridging the mesentery milieu and lymphatic function, which could potentially provide diagnostic tools and/or therapies to improve lymph transport, and thus improve health in chronic inflammatory conditions such as MetSyn.

描述（由申请人提供）：尽管超过95％的饮食脂质是通过肠道淋巴管从小肠吸收的，通过肠系膜收集淋巴网络通过淋巴网络运输，在血液中通过淋巴网络传播，但淋巴运输在脂质代谢的调节中的作用是较差的。我们最近表明，高果糖饮食诱导的代谢综合征（METSYN）大鼠表现出受损的肠系膜淋巴功能。饮食内毒素很容易与酪蛋白相关，并主要通过肠系膜淋巴管吸收，以及许多其他肠道肽和激素，这表明饮食内毒素的主要运输，例如脂多糖（LPS）（LPS）是通过淋巴处理的。 因此，重要的问题仍然没有解决：1）淋巴功能在饮食内毒素中的作用和反应性是什么，2）这如何影响METSYN的进展。我们的初步数据表明，免疫细胞，嗜酸性粒细胞和嗜中性粒细胞存在于淋巴壁或附近，并且在LPS诱导的发炎肠系膜组织中，淋巴壁上这些免疫细胞的数量减少。这些数据为我们的中心假设提供了基础：饮食中内毒素会改变局部线索（嗜酸性粒细胞和中性粒细胞的主要细胞因子：IL-4，IL-5，IL-8，IL-8和IL-13）在肠系膜环境中会损害淋巴功能和囊囊层的积累，这会损害乳腺症和丝状质量症状，这会损害淋巴结的症状和丝状系统疾病。 Metsyn的发展。我们将使用高果糖和高脂饮食诱导的METSYN大鼠模型以及LPS诱导的炎症模型来确定淋巴系统在METSYN的病理生理学中的作用。具体目的是：1）证明饮食内毒素，促炎细胞因子和淋巴功能之间的联系； 2）确定METSYN发育中淋巴传递降低的功能后果和分子机制； 3）测试微RNA（miR）的作用，以互连IL-8，IL-4，IL-5和IL-13在METSYN开发过程中调节淋巴功能中的调节。我们将使用整个安装肠系膜制剂进行免疫组织化学研究，原位准备淋巴流量和淋巴收缩力，分离/容管血管，用于淋巴管的收缩特征，用于长度张力和力量钙测量值的电线学研究。这些实验将特别解决饮食内毒素如何影响M1和M2巨噬细胞极化对淋巴机以及嗜酸性粒细胞和嗜中性粒细胞白细胞介菌，IL-4，IL-5，IL-8，IL-8和IL-13和IL-13和IL-13和MIR-19A，MIR-19A，93，200C和203的机制。因此，该提案将确定桥接肠系膜环境和淋巴功能的重要目标，该目标可能有可能提供诊断工具和/或疗法以改善淋巴运输，从而改善慢性炎症状况（例如Metsyn）的健康状况。