Enterocyte lipid trafficking pathways that regulate intestinal absorption and efflux of dietary lipids

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The intestine is the first-pass organ for the metabolism of dietary lipids and has an important role in whole body cholesterol homeostasis. While the intestine is known predominantly to absorb and secrete cholesterol and contributes to faecal sterol removal, it has also been proposed to contribute to the regulation of plasma cholesterol concentration. Since being awarded my first NSERC grant, I have discovered that the intestine can modulate it's secretion of cholesterol and triglyceride (TG) under different metabolic and dietary fatty-acid conditions. Further, I have also revealed that certain dietary fatty acids (natural trans fats) can directly affect intestinal lipid secretary pathways. In my renewal application, I propose an extension of these novel findings to delineate intracellular lipid trafficking pathways that regulate absorption/efflux, transport, synthesis and/or secretion of cholesterol by the intestine. Specifically, I propose to use a molecular and physiological approach to understand the significance of 'trans-enterocytic cholesterol efflux' (TICE) in whole-body cholesterol homeostasis. TICE is an emerging concept suggesting the intestine can readily efflux plasma-derived cholesterol back out to the intestinal lumen for faecal excretion (or re-absorption). Our preliminary data suggests that the enterocyte can modulate TICE and is dependent on metabolic or dietary conditions. During the proposed 5-year program I aim to investigate the role of dietary fatty acids known to modulate lipid metabolism e.g. vaccenic acid (VA) and n-3 polyunsaturated fatty acids (PUFA), DHA and EPA, on enterocyte cholesterol absorption, synthesis, trafficking and TICE. The working hypothesis for this program is that intestine contributes substantially to whole body cholesterol homeostasis through active regulation of bi-directional lipid flux, endogenous synthesis, intracellular trafficking and subsequent secretion. The outcomes will delineate cholesterol synthesis and trafficking within the enterocyte and subsequent impact of dietary-derived lipids to nutrition.