METABOLISM OF INTRAVENOUS LIPID EMULSIONS

描述（由申请人提供）：我们的目标是描述静脉注射（IV）脂质乳剂的途径，临床上通常用作营养支持，将特定类型的甘油三酯（TG）输送到组织和细胞。随着越来越多的人认识到omega-3 （omega-3）长链脂肪酸（FA） （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向不同组织输送的机制，并确定这种输送对与细胞TG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omega - 3 TG的血液清除和组织吸收途径与omega - 6大豆油长链TG （LCT）非常不同。例如，从血液中去除（omega3 VLCT）乳剂似乎比LCT乳剂更少依赖于血管内脂解。虽然这两种乳剂都以完整的TG的形式被输送到组织中，但这一途径对omega3 TG颗粒可能更重要。与LCT相比，Omega3 TG颗粒较少依赖于“经典”脂蛋白受体相关的清除途径。来源于omega - 3tg的FA似乎比LCT更能抑制固醇调节元件（SRE）依赖基因的表达，这些基因参与TG和胆固醇的合成。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对LCT与omega3-VLCT的清除和代谢的影响机制。目的1将使用物理化学方法（例如，13C-NMR）来阐明omega - tg和FA如何影响乳液颗粒表面的性质，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目的3在体内小鼠模型来区分omega - vlct /FA和omega - 6 TG/FA的代谢途径，以及这些差异如何影响TG和胆固醇稳态相关基因的表达。Aim 4的研究将通过将omega - vlct和LCT乳剂注入健康志愿者体内的方案，检验从细胞和小鼠模型中产生的假设是否可能在人类中发生。我们的分析将区分清除和代谢机制- 3和- 6 TG和FA。我们的研究将为鱼油衍生乳剂如何到达不同组织、进行代谢处理和调节某些基因的表达提供新的见解，并将为研究人类脂质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.