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

胃肠道是饮食脂肪代谢的“首过”器官，在调节全身脂质和胆固醇方面起着重要作用。在过去10年的NSERC资助中，我的团队对膳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/转运）和（生产/分泌）方法，我们已经取得了里程碑式的发现，在社会上有广泛的影响;包括让加拿大卫生部参与食品政策，在省、国家和国际畜牧业/乳制品部门发挥领导作用，支持制药行业的商业计划，并为通过肠道实现新药靶点的新兴分子途径做出了贡献。我的NSERC计划的贡献已经培养了来自世界各地的研究生和本科生的显着数量，谁已经去采取在其他大学的位置，行业和政府。重要性和新奇 * 胃肠道包括一系列独特的导管血管（称为动脉），不仅有助于炎症细胞网络，而且对将膳食脂肪输送到血流中也至关重要。能够仔细插管的主要淋巴管（在啮齿动物和最近在猪），使淋巴系统的研究及其在营养中的作用。我们有令人兴奋的新数据显示，在脂肪中发现的两种脂质成分（称为乳糜微粒的大脂质分子和较小的“好胆固醇”HDL颗粒）可以在进食状态下改变，并且含有大量称为microRNA的新型遗传物质。肠道相关microRNA的重要性在于它为肠道如何调节体内脂质提供了新的证据。NSERC更新的重点是我的NSERC计划提出淋巴系统在控制体内脂质代谢的两个主要途径中起着关键作用;（1）它可以调节胆固醇（HDL）的好形式，通过“胆固醇反向转运”[RCT]途径从体内清除“坏”形式的胆固醇，以及（2）通过一种新的途径称为跨肠胆固醇流出[TICE]。TICE是一个新兴的概念，表明肠道将血液来源的胆固醇排出到管腔中以排泄出体外。新的数据表明，TICE途径对体内胆固醇代谢有重要作用，并且可以通过营养物质进行调节。最近，还发现淋巴系统的破坏导致RCT和可能的TICE受损。通过这个NSERC计划，我们将发现淋巴系统如何连接这些通路，以及在正常脂质稳态期间，miRNA、营养物质或化合物如何调节这些通路。

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.**