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

肠细胞脂质运输途径对膳食脂质吸收和全身脂质稳态的生理相关性

• 批准号: RGPIN-2015-03971
• 负责人: Proctor, Spencer
• 金额: $ 3.57万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=662636
• 关键词: Physiological; relevance; enterocytic; lipid; trafficking

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.**

计划范围***胃肠道是膳食脂肪代谢的“首过”器官，在调节全身脂质和胆固醇方面发挥着重要作用。在 NSERC 资助的过去 10 年中，我的团队为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/运输）和（生产/分泌）方法，我们取得了里程碑式的发现，对社区产生了广泛的影响；包括与加拿大卫生部合作制定食品政策，在省、国家和国际畜牧业/乳制品行业中发挥领导作用，支持制药行业的商业计划，并为通过肠道的新药物靶标的新兴分子途径做出贡献。我的 NSERC 项目的贡献培养了来自世界各地的大量研究生和本科生，他们后来在其他大学、行业和政府中担任职务。***意义和新颖性***胃肠道包括一系列独特的导管（称为淋巴管），它们不仅促进炎症细胞网络，而且对于将膳食脂肪输送到血流中也至关重要。仔细插入初级淋巴管（在啮齿动物和最近的猪中）的能力使得研究淋巴系统及其在营养中的作用成为可能。我们有令人兴奋的新数据表明，在淋巴管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）可以在进食状态下发生改变，并且含有大量称为 microRNA 的新型遗传物质。淋巴相关的 microRNA 的重要性在于，它提供了肠道如何调节体内脂质的新证据。*** 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着关键作用； (1) 它可以通过“反向胆固醇转运”[RCT] 途径调节良好形式的胆固醇 (HDL)，从体内清除“不良”形式的胆固醇；(2) 通过称为跨肠胆固醇流出 [TICE] 的新途径。 TICE 是一个新兴概念，表明肠道将血液中的胆固醇排入肠腔，然后排出体外。新数据表明，TICE 途径对体内胆固醇代谢有显着贡献，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会导致 RCT 和可能的 TICE 受损。通过这个 NSERC 项目，我们将发现淋巴系统如何连接这些途径，miRNA、营养素或化合物如何在正常脂质稳态期间调节这些途径。 **