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

点击翻译按钮获取中文摘要

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.**