Gut mucosal mast cells are activated by fat absorption: physiology and mechanism

脂肪吸收激活肠道粘膜肥大细胞：生理学和机制

• 批准号: 8242696
• 负责人: PATRICK TSO
• 金额: $ 34.15万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242696
• 关键词: Acute; Address; Adverse effects; Affect; Anesthesia procedures; Animals; Atherosclerosis; Basophils; Blood; Blood Circulation; Caco-2 Cells; Carbohydrates; Cardiovascular Diseases; Cell Degranulation; Cell Line; Cells; Chronic; Chylomicrons; Clinical; Connective Tissue; Conscious; Consumption; Coronary heart disease; Diabetes Mellitus; Diet; Dietary Fats; Disease; Enterocytes; Enzymes; Epithelial Cells; Etiology; Exposure to; Fasting; Fatty Acids; Fatty acid glycerol esters; Fistula; Future; Gastrointestinal tract structure; Health; In Vitro; Inflammatory; Ingestion; Intestines; Knowledge; Lamina Propria; Linoleic Acids; Lipids; Lymph; Lymphatic; Mast Cell Stabilizer; Measures; Mediator of activation protein; Metabolic syndrome; Modeling; Modification; Monitor; NF-kappa B; NFKB Signaling Pathway; Obesity; Omega-3 Fatty Acids; Outcome; Patients; Peptide Hydrolases; Physiological; Physiology; Process; Production; Proteins; Rattus; Relative (related person); Role; Testing; Therapeutic; Time; Tissues; Tryptase; Work; absorption; arachidonate; chemokine; clinically relevant; cytokine; experience; feeding; gastrointestinal; gastrointestinal function; insight; interest; leukemia; lipid mediator; long chain fatty acid; mast cell; novel; nutrition; public health relevance; release factor; response; uptake

DESCRIPTION (provided by applicant): In patients with diabetes, obesity, or cardiovascular disease, the circulating proinflammatory mediators are often elevated. We made the novel observation that intestinal mucosal mast cells (MMC) are activated by fat absorption. In our well established conscious lymph fistula rats, we showed that fat absorption activates the intestinal mucosal mast cells (MMC) and they degranulate as evidenced by the marked increase (~ 20 fold) of the MMC marker protease II in intestinal lymph relative to fasting lymph (pre-ingestion of fat). This observation is very exciting from the standpoint of gut physiology; it may have profound clinical implications. We consume fat a few times a day and so the MMC are activated frequently during the day. With the activation and degranulation of MMC, the gut may be an important contributor to the circulating proinflammatory mediators. We hypothesized that the absorption of lipids and the formation and secretion of chylomicrons (CMs) activate the MMCs. This action is lipid specific and is not shared by proteins or carbohydrates. We further hypothesize that acute and chronic consumption of fat, the type of fat, influence its ability to activate the MMCs and that the order of potency is omega 6 (linoleate & arachidonate) > omega 9 (oleate) > omega 3 fatty acids (linolenate). To test these hypotheses, we proposed the following studies: Specific Aim 1. We will determine the relationship between intestinal fat absorption and MMC activation. Subaims: 1) to further characterize the activation of MMC by measuring the release of mast cell mediators in lymph and tissue during fat absorption, we will determine if the release of lipid mediators, cytokines, chemokines is mostly from MMC by using the mast cell deficient Ws/Ws rats; 2) to determine if the presence or absence of MMC stabilizers affects intestinal uptake and lymphatic transport of dietary lipids. We will also study fat absorption in Ws/Ws rats. Specific Aim 2. We hypothesize that the production of CMs, resulting from dietary polyunsaturated long-chain fatty acids (FA) linoleic acid (18:2, n-6) is a potent determinant of the mast cell activation and this action is differently affected by the type of fatty acids. We will determine the acute and chronic exposure to fatty acids with different degree of unsaturation and the type (n-3, n-6, and n-9) fatty acids on MMC activation by fat absorption. Specific Aim 3. We will test our hypothesis that fatty acid or the processing of CMs by the enterocytes results in the release of factor/factors that cause the activation of the MMCs (e.g. NF-kB response). To test our hypotheses, we have proposed the following 2 subaims. 1) We will study the in vitro effects of different types of FAs on rat basophil leukemia cells (RBL-2H3 cells, a surrogate of the rat MMC) activation through NF-kB signaling pathway; 2) We will study the interaction of chylous lymph and its components e.g. chylomicrons (CMs) or the media containing CMs by the intestinal epithelial cell line (Caco-2 cells) on RBC-2H3 cell NF-kB response. If the outcome is positive, we will isolate the factor/factors involved. PUBLIC HEALTH RELEVANCE: By focusing on the relationship between fat absorption and mucosal mast cell degranulation, our proposed studies will identify the role of gut-derived inflammatory factors in the normal process of dietary fat absorption and transport, identify which inflammatory agents are generated by normal fat absorption and may enter the general circulation, and contribute to the etiology of various diseases such as diabetes, metabolic syndrome, and atherosclerosis and coronary heart disease. Our results will also greatly enhance our understanding of function of gastrointestinal lymphatics in health and disease by clarifying the changes which occur in GI lymph parameters during normal physiological states such as fasting and lipid absorption, laying the ground work for future studies comparing the differences in lymph between diseased states and normal physiological states.

描述（由申请人提供）：在糖尿病，肥胖或心血管疾病的患者中，循环促炎性介质通常会升高。我们使新的观察结果是，肠粘膜肥大细胞（MMC）被脂肪吸收激活。在我们建立的有意识的淋巴瘘大鼠中，我们表明脂肪吸收激活了肠粘膜肥大细胞（MMC），并且它们在肠道淋巴的MMC Marker蛋白酶II的显着增加（约20倍）相对于脂肪淋巴（脂肪前）而降解。从肠道生理的角度来看，这种观察非常令人兴奋。它可能具有深远的临床意义。我们每天消耗几次脂肪，因此MMC在白天经常被激活。随着MMC的激活和脱粒，肠道可能是循环促炎性介质的重要促进者。我们假设脂质的吸收以及乳糜微粒（CMS）的形成和分泌激活MMC。该作用是脂质特异性的，蛋白质或碳水化合物不共享。我们进一步假设脂肪的急性和长期消耗脂肪的类型会影响其激活MMC的能力，并且效力的顺序为Omega 6（LinoLeate＆Arachidonate）> Omega 9（oleate）> OmeaTe 9（Omeate）> Omega 3脂肪酸3脂肪酸（Linololenenate）。为了检验这些假设，我们提出了以下研究：具体目的1。我们将确定肠道脂肪吸收与MMC激活之间的关系。 Subiaim：1）为了进一步表征MMC的激活，通过在吸收脂肪吸收过程中测量淋巴和组织中肥大细胞介质的释放，我们将确定脂质介质，细胞因子的释放，趋化因子是否通过使用MAST缺乏WS/WS/WS大鼠的MMC来确定MMC。 2）确定MMC稳定剂的存在或不存在会影响饮食脂质的肠道摄取和淋巴运输。我们还将研究WS/WS大鼠的脂肪吸收。具体目的2。我们假设CMS的产生是由饮食多不饱和的长链脂肪酸（FA）亚油酸（18：2，N-6）产生的，是肥大细胞激活的有效决定因素，并且该作用受到脂肪酸类型的影响。我们将确定具有不同程度的不饱和度的急性和慢性暴露于脂肪酸以及通过吸收脂肪吸收的MMC激活中（N-3，N-6和N-9）脂肪酸的类型（N-3，N-6和N-9）。具体目的3。我们将检验我们的假设，即肠肠上细胞脂肪酸或CMS的处理导致导致MMC激活的因子/因子释放（例如NF-KB响应）。为了检验我们的假设，我们提出了以下2个子。 1）我们将研究不同类型的FAS对大鼠嗜碱性白血病细胞（RBL-2H3细胞，大鼠MMC的替代物）的体外作用通过NF-KB信号传导途径激活； 2）我们将研究Chylous淋巴及其成分的相互作用，例如RBC-2H3细胞NF-KB响应上的肠上皮细胞系（CACO-2细胞）含有CM的胆囊（CMS）或介质。如果结果是积极的，我们将隔离所涉及的因子/因素。 公共卫生相关性：通过关注脂肪吸收与粘膜肥大细胞脱粒之间的关系，我们的拟议研究将确定肠道衍生的炎症因素在饮食中脂肪吸收和运输正常过程中的作用，确定哪些炎症药是由正常脂肪吸收而产生的，并可能导致一般循环症和疾病，例如疾病，并伴有疾病的综合症状，并伴有疾病的综合综合序列，并且会导致综合症状，并伴随着综合症状，并且会导致综合症状，并且会导致综合症状，并且会导致综合症状，并且会导致综合症状，并且会导致综合症状，并且会导致综合综合症状，并且会导致综合疾病，并且会导致综合疾病和疾病。冠心病。我们的结果还将大大增强我们对胃肠道淋巴管在健康和疾病中的功能的理解，通过阐明在正常生理状态（例如禁食和脂质吸收）期间GI淋巴参数中发生的变化，为未来的研究奠定了与疾病状态和正常生理状态淋巴差异的未来研究的地面工作。