METABOLISM OF INTRAVENOUS LIPID EMULSIONS

描述（由申请方提供）：我们的目的是表征静脉（IV）脂肪乳剂（临床上常用作营养支持）向组织和细胞递送特定类型甘油三酯（TG）的途径。随着人们越来越认识到omega-3（omega-3）极长链脂肪酸（FA）（omega-3-VLC FA）在多种生物学途径中的重要性，我们的主要目标是描述将这些omega-3 FA递送至不同组织的机制，并确定这种递送对与细胞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ω 3 TG的血液清除和组织吸收途径与ω 6大豆油长链TG（LCT）的血液清除和组织吸收途径非常不同。例如，从血液中去除（ω 3 VLCT）乳剂似乎比LCT乳剂更不依赖于血管内脂解。虽然大量的两种乳剂作为完整的TG递送至组织，但该途径对于ω 3 TG颗粒可能更重要。Omega 3 TG颗粒比LCT更少依赖于“经典”脂蛋白受体相关的清除途径。来自ω 3 TG的FA似乎比LCT在固醇调节元件（SRE）依赖的基因表达中起更强的抑制剂作用，所述基因参与TG和胆固醇合成。拟议的研究将系统地定义TG组成、粒度和特异性配体相关途径在不同组织和细胞类型中促进LCT与ω 3-VLCT清除和代谢的机制。目标1将使用物理化学方法（例如，13 C-NMR）来阐明ω 3-TG和FA如何影响乳剂颗粒表面的性质，以及这又如何影响脂蛋白脂肪酶和脱辅基蛋白E结合、结构和功能。目的2利用体外细胞培养实验和目的3体内小鼠模型来区分ω 3-VLCT/FA和ω 6 TG/FA的代谢途径，以及这些差异如何影响与TG和胆固醇稳态相关的基因表达。目标4中的研究将通过将omega 3-VLCT和LCT乳剂输注到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发生在人体中。我们的分析将区分ω 3与ω 6 TG和FA的清除和代谢机制。我们的研究将使新的见解，鱼油衍生的乳液如何到达不同的组织，进行代谢加工，并调节某些基因的表达，也将提供仔细表征的模型，用于研究人类脂质和脂蛋白代谢。

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.