Physiological relevance of enterocytic lipid trafficking pathways on dietary lipid absorption and whole body lipid homeostasis

计划范围*胃肠道是饮食脂肪新陈代谢的“第一道”器官，在调节全身的血脂和胆固醇方面起着重要作用。在过去10年的NSERC资助中，我的团队对饮食脂质调节肠道吸收和分泌的新见解做出了贡献。通过结合一系列独特的技术(吸收/运输)和(生产/分泌)方法，我们已经取得了具有里程碑意义的发现，在社区中产生了广泛的影响；包括让加拿大卫生部参与食品政策，在省级、国家和国际牲畜/乳制品部门发挥领导作用，支持制药行业的商业计划，并通过肠道为新药物靶标的新兴分子途径做出贡献。我的NSERC项目的贡献培养了大量来自世界各地的研究生和本科生，他们后来在其他大学、行业和政府部门任职。*意义和新颖性*胃肠道包括一系列独特的管道血管(称为淋巴管)，它们不仅促进炎症细胞网络，而且对将饮食脂肪输送到血液中也至关重要。仔细插入初级淋巴管的能力(在啮齿类动物中和最近在猪中)使研究淋巴系统及其在营养中的作用成为可能。我们有了令人兴奋的新数据，表明在淋巴管中发现的两种脂质组分(称为乳胶粒的大脂分子和较小的“好胆固醇”高密度脂蛋白颗粒)可以在喂养状态下改变，并含有高度丰富的新遗传物质，称为microRNAs。淋巴管相关的microRNA的意义在于它为肠道如何调节体内的脂质提供了新的证据。*NSERC计划的目标*我的NSERC计划更新的重点是提出淋巴系统在控制体内脂质代谢的两条主要途径中发挥关键作用；(1)它可以调节好的胆固醇形式(HDL)，通过‘反向胆固醇运输’[RCT]途径从体内清除‘坏’形式的胆固醇；(2)通过一种名为跨肠道胆固醇外流[TICE]的新途径。TICE是一个新兴的概念，它认为肠道将血液衍生的胆固醇排入管腔，然后排出体外。新的数据表明，Tice途径对体内的胆固醇代谢有很大贡献，并可以受到营养物质的调节。最近，人们还发现淋巴系统的破坏会导致RCT和TICE的损害。通过NSERC计划，我们将发现淋巴系统如何连接这些途径，miRNAs、营养素或化合物如何在正常的脂质平衡中调节这些途径。**

PROGRAM SCOPE ***The gastrointestinal tract is the 'first-pass' organ for the metabolism of dietary fats and has an important role in regulation of lipids and cholesterol throughout the whole body. Over the past 10 years of NSERC funding, my group has contributed to new insights into the regulation of intestinal absorption and secretion by dietary lipids. By combining a unique series of technical (absorption/transport) and (production/secretory) methods, we have made landmark discoveries that have wide-ranging impact in the community; including engaging Health Canada on food policies, having leadership roles with provincial, national and international Livestock/Dairy sector, underpinning business plan of the pharmaceutical industry and contributed to emerging molecular pathways for new drug targets via the intestine. The contributions of my NSERC program have trained a significant number of graduate and undergraduate students from all over the world, who have gone on to take positions in other University's, industry and government.***SIGNIFICANCE AND NOVELTY***The gastrointestinal tract includes a unique series of conduit vessels (called the lymphatics) that not only facilitate the inflammatory cell network but are also critical to transport dietary fats into the blood stream. The ability to carefully cannulate the primary lymphatic duct (in rodents and recently in swine) enables the study of the lymphatic system and its role in nutrition. We have exciting new data that shows two lipid fractions found in the lymphatics (large lipid molecules called chylomicrons and smaller 'good cholesterol' HDL particles) can be altered during fed state, and contain a high abundance of novel genetic material called microRNAs. The significance of lymphatic-associated microRNA's is that it provides new evidence of how the intestine may regulate lipids in the body.***OBJECTIVES OF NSERC PROGRAM***The focus of the renewal to my NSERC program is to propose that the lymphatic system plays a critical role in two major pathways that control lipid metabolism in the body; (1) It can regulate good forms of cholesterol (HDL) in the removal of  'bad' forms of cholesterol from the body via the `reverse-cholesterol transport' [RCT] pathway and (2) via a new pathway called  trans-intestinal cholesterol efflux [TICE]. TICE is an emerging concept suggesting that the intestine effluxes blood-derived cholesterol into the lumen for excretion out of the body. New data suggests that the TICE pathway contributes significantly to cholesterol metabolism in the body and can be modulated by nutrients. Recently, it has also been discovered that disruption to the lymphatic system leads to an impairment of RCT and possibly TICE. Through this NSERC program we will discover how the lymphatic system links these pathways, how miRNAs, nutrients or compounds may modulate these pathways during normal lipid homeostasis.**