METABOLISM OF INTRAVENOUS LIPID EMULSIONS

描述(由申请人提供)：我们的目标是确定静脉注射(IV)脂肪乳剂将特定类型的甘油三酯(TG)输送到组织和细胞的途径，静脉(IV)脂肪乳剂通常用作营养支持。随着人们越来越多地认识到omega-3(omega-3)超长链脂肪酸(omega-3-VLC FA)在多种生物途径中的重要性，我们的主要目标是描述这些omega-3 FA传递到不同组织的机制，并确定这种传递对与细胞甘油三酯和胆固醇代谢相关的选定细胞终点的影响。最近的证据表明，鱼油omega3 TG的血液清除和组织摄取途径与omega6豆油长链TG(LCT)有很大不同。例如，从血液中去除(Omega3 VLCT)乳剂似乎比LCT乳剂对血管内脂肪分解的依赖要少得多。虽然这两种乳剂都以完整的甘油三酯的形式被输送到组织中，但这一途径对omega3甘油三酯颗粒可能更重要。与LCT相比，Omega3TG颗粒对“经典”脂蛋白受体相关清除途径的依赖程度较低。在依赖于固醇调节元件(SRE)的基因表达中，来自omega3 TG的FA似乎比LCT起到了更强的抑制作用-这些基因参与了TG和胆固醇的合成。这项拟议的研究将系统地定义TG组成、颗粒大小和特定配体相关途径在不同组织和细胞类型中促进LCT与omega3-VLCT清除和代谢的机制。目标1将使用物理化学方法(例如13C-核磁共振)来阐明omega3-TG和FA如何影响乳状液颗粒表面的性质，以及这反过来如何影响脂蛋白脂肪酶和载脂蛋白E的结合、结构和功能。目的2利用体外细胞培养实验和AIM 3小鼠体内模型来区分omega3-VLCT/FA和omega6 TG/FA的代谢途径，以及这些差异如何影响甘油三酯和胆固醇稳态相关基因的表达。AIM 4上的研究将通过在健康志愿者中注入omega3-VLCT和LCT乳剂的方案来测试从细胞和小鼠模型产生的假设是否可能在人类身上发生。我们的分析将区分清除和代谢机制omega3与omega6，TG和FA。我们的研究将为鱼油乳剂如何到达不同的组织、进行代谢处理和调节某些基因的表达提供新的见解，并将为研究人类脂肪和脂蛋白代谢提供仔细表征的模型。

DESCRIPTION (provided by applicant): Our objective is to characterize pathways whereby intravenous (IV) lipid emulsions, commonly used clinically as nutritional support, deliver specific types of triglyceride (TG) to tissues and cells. With increasing recognition of the importance of omega-3 (omega-3) very long chain fatty acids (FA) (omega3-VLC FA) in multiple biological pathways, our major goal is to delineate mechanisms for delivery of these omega3 FA to different tissues, and to define the effects of this delivery on selected cellular endpoints related to cell TG and cholesterol metabolism. Recent evidence indicates that routes for blood clearance and tissue uptake of fish oil omega3 TG are very different from those of omega6 soy oil long chain TG (LCT). For example, removal of (omega3 VLCT) emulsions from blood seems to depend far less on intravascular lipolysis than does LCT emulsions. While substantial amounts of both emulsions are delivered to tissues as intact TG, this pathway is likely more important for omega3 TG particles. Omega3 TG particles are less dependent on "classical" lipoprotein receptor related clearance pathways, than are LCT. FA derived from omega3 TG appear to act as stronger inhibitors than LCT in sterol regulatory element (SRE) dependent gene expression-genes that are involved in both TG and cholesterol syntheses. The proposed research will systematically define mechanisms whereby TG composition, particle size, and specific ligand related pathways contribute to LCT vs. omega3-VLCT clearance and metabolism in different tissues and cell types. Aim 1 will use physical-chemical approaches (e.g., 13C-NMR) to clarify how omega3-TG and FA affect the properties of the emulsion particle surface, and how this in turn affects lipoprotein lipase and apoprotein E binding, structure, and function. Aim 2 utilizes in vitro cell culture experiments and Aim 3 in vivo mouse models to differentiate metabolic pathways for omega3-VLCT/FA and omega6 TG/FA, and how these differences affect expression of genes related to TG and cholesterol homeostasis. Studies in Aim 4 will test if hypotheses generated from cell and mouse models are likely to occur in humans -- by protocols whereby omega3-VLCT and LCT emulsions are infused in healthy volunteers. Our analyses will differentiate between mechanisms for clearance and metabolism omega3 vs. omega6 TG and FA. Our studies will allow new insight as to how fish oil derived emulsions reach different tissue, undergo metabolic processing, and regulate expression of certain genes, and will also provide carefully characterized models for the study of human lipid and lipoprotein metabolism.