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

肠道是膳食脂质代谢的第一通道器官，在全身胆固醇稳态中起着重要作用。虽然已知肠道主要吸收和分泌胆固醇，并有助于粪便中的胆固醇去除，但它也被认为有助于调节血浆胆固醇浓度。自从获得我的第一笔NSERC基金以来，我发现肠道可以在不同的代谢和膳食脂肪酸条件下调节胆固醇和甘油三酯（TG）的分泌。此外，我还揭示了某些膳食脂肪酸（天然反式脂肪）可以直接影响肠道脂质分泌途径。在我的更新申请中，我建议扩展这些新发现，以描述调节肠道吸收/流出、运输、合成和/或分泌胆固醇的细胞内脂质运输途径。具体来说，我建议使用分子和生理学的方法来理解“跨肠细胞胆固醇外排”（TICE）在全身胆固醇稳态中的意义。TICE是一个新兴的概念，表明肠道可以很容易地将血浆来源的胆固醇外排回肠腔进行粪便排泄（或重新吸收）。我们的初步数据表明，肠细胞可以调节TICE，并依赖于代谢或饮食条件。在计划的5年计划中，我的目标是研究已知的调节脂质代谢的膳食脂肪酸，如异丙酸（VA）和n-3多不饱和脂肪酸（PUFA）， DHA和EPA，在肠细胞胆固醇吸收，合成，运输和TICE中的作用。该程序的工作假设是，肠道通过主动调节双向脂质通量、内源性合成、细胞内运输和随后的分泌，对全身胆固醇稳态做出了重大贡献。结果将描绘胆固醇合成和运输肠细胞和随后的影响饮食来源的脂质营养。

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.