Synergistic Effects of Medium-chain and Omega-3 Triglycerides on Cellular Omega-3 Fatty Acid Enrichment: Characterization, Mechanisms, and Optimization

中链甘油三酯和 Omega-3 甘油三酯对细胞 Omega-3 脂肪酸富集的协同效应：表征、机制和优化

• 批准号: 10319563
• 负责人: Chuchun Liz Chang
• 金额: $ 38.64万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-10 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319563
• 关键词: Acute; Address; Affect; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Apoptosis; Apoptotic; Area; Bioenergetics; Biophysics; Blood Platelets; Bolus Infusion; Brain Death; Cell Death; Cell Membrane Structures; Cell Separation; Cell membrane; Cell model; Cells; Cellular Structures; Cerebrum; Chronic; Clinical; Coupled; Data; Disease; Docosahexaenoic Acids; Eicosanoids; Eicosapentaenoic Acid; Emulsions; Endothelial Cells; Experimental Animal Model; Fatty Acids; Fish Oils; Free Radicals; Functional disorder; Homeostasis; Hydrolysis; Hydrophobicity; Immune; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injections; Intake; Intravenous; Intravenous Bolus; Intravenous infusion procedures; Ischemic Stroke; Laboratories; Leukocytes; Lipids; Liquid substance; Mass Spectrum Analysis; Mediating; Medium chain triglycerides; Membrane; Membrane Lipids; Metabolic; Methods; Modeling; Molecular Conformation; Monoclonal Antibodies; Morbidity - disease rate; Myocardial Infarction; Non-Steroidal Anti-Inflammatory Agents; Nuclear Magnetic Resonance; Oils; Omega-3 Fatty Acids; Operative Surgical Procedures; Oral; Organ; Pathway interactions; Phospholipids; Physical Chemistry; Physiological; Plasma; Prevention; Production; Regulation; Reporting; Research; Resolution; Route; Series; Spinal cord injury; Stimulus; System; TNF gene; Therapeutic; Therapeutic Agents; Tissues; Triglyceride Metabolism; Triglycerides; acute infection; advanced analytics; base; biophysical properties; biophysical techniques; design; experimental study; fatty acid oxidation; feeding; healing; human model; in vivo; innovation; lipid disorder; lipid metabolism; lipidomics; lipophilicity; macrophage; membrane activity; membrane model; monocyte; mouse model; multidisciplinary; novel; novel therapeutic intervention; optical imaging; organ injury; particle; post stroke; preservation; prevent; response; synergism; systemic inflammatory response; tissue injury; uptake

Adverse inflammatory response leads to cell death and organ dysfunction. We will investigate whether acute intravenous (IV) treatments of lipid emulsions containing medium-chain triglycerides (TG) (MCT) and omega-3 (n-3) TG enriched in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) provide a new therapeutic approach to ameliorate adverse inflammatory responses by targeting rapid cellular n-3 FA membrane enrichment. n-3 fatty acids (FA) are increasingly recognized as a potent supplement in IV feeding because of their pro-healing and anti-inflammatory effects against apoptosis and production of free radicals and pro- inflammatory eicosanoids. Studies in experimental animal models demonstrate that bolus injections of n-3 TG- rich emulsion particles (TGRP) are therapeutically protective in decreasing brain death and morbidity after stroke. We have discovered that TGRP containing both MCT and fish oil TG (8:2 wt/wt) enriched cell membranes of white blood cells and endothelial cells with n-3 FA more efficiently than other TGRP. Using nuclear magnetic resonance (NMR), we reported that the inclusion of MCT into model TGRP promotes model membrane lipid disorder that may accelerate n-3 delivery rates, highlighting the advantage of bolus injection for n-3 FA enrichment. However, very few studies have addressed the acute anti-inflammatory effects of acute IV n-3 administration. Currently, there is no data on optimal mixtures of MCT with n-3 TG to achieve the most rapid and highest-magnitude anti-inflammatory action. Our central hypothesis is that bolus injections of TGRPs containing both MCT and n-3 TG will cooperatively affect membrane dynamics to accelerate n-3 FA incorporation into cell membranes, which will initiate n-3-mediated anti-inflammatory and anti-apoptotic actions. These will be studied under 3 Specific Aims. Under Aim 1, we will characterize biophysical properties of MCT-containing TGRP with different n-3 TG contents using biophysical approaches coupled with mass spectrometry-based lipidomics to assess alteration in membrane structure and activity mediated by specific MCT:n-3 TGRP containing DHA, EPA, or both. In Aim 2, we will define cellular uptake pathways responsible for internalization and metabolic utilization of specific MCT:n-3 TGRP characterized in Aim 1 in cultured immune-effector macrophages and in mouse models. We will then investigate under Aim 3 how MCT:n-3 TGRP cellular internalization affects functional activities of monocytes and macrophages in response to an acute immune stimulus (LPS) in mouse models. The proposed studies in cells and animal models will establish innovative methods that are adaptable for targeted, rapid delivery of lipophilic and hydrophobic therapeutic agents to specific organs or tissues. We will uncover novel synergies between MCT and n-3 TG that modulate membrane lipid composition, cell lipid metabolism, and immune responses. Our studies will be of high significance to many fields, including immune responses to infection and inflammation-related tissue injury and organ dysfunction.

不良炎症反应导致细胞死亡和器官功能障碍。我们将研究含有中链甘油三酯 (TG) (MCT) 和富含二十碳五烯酸 (EPA) 和二十二碳六烯酸 (DHA) 的 omega-3 (n-3) TG 的脂肪乳剂的急性静脉 (IV) 治疗是否提供了一种新的治疗方法。通过靶向快速细胞 n-3 FA 膜富集来改善不良炎症反应的治疗方法。 n-3 脂肪酸 (FA) 越来越被认为是静脉喂养中的有效补充剂，因为它们具有促进愈合和抗炎作用，可对抗细胞凋亡以及自由基和促炎类二十烷酸的产生。实验动物模型研究表明，推注富含 n-3 TG 的乳液颗粒 (TGRP) 对于减少中风后脑死亡和发病率具有治疗保护作用。我们发现，同时含有 MCT 和鱼油 TG（8:2 wt/wt）的 TGRP 比其他 TGRP 更有效地用 n-3 FA 富集白细胞和内皮细胞的细胞膜。使用核磁共振 (NMR)，我们报告将 MCT 纳入模型 TGRP 会促进模型膜脂质紊乱，从而可能加速 n-3 递送速率，突出了推注注射对于 n-3 FA 富集的优势。然而，很少有研究探讨急性 IV n-3 给药的急性抗炎作用。目前，尚无关于 MCT 与 n-3 TG 的最佳混合物以实现最快速和最高强度的抗炎作用的数据。我们的中心假设是，推注含有 MCT 和 n-3 TG 的 TGRP 将协同影响膜动力学，加速 n-3 FA 掺入细胞膜，从而启动 n-3 介导的抗炎和抗凋亡作用。这些将在 3 个具体目标下进行研究。在目标 1 下，我们将使用生物物理方法结合基于质谱的脂质组学来表征具有不同 n-3 TG 含量的含 MCT 的 TGRP 的生物物理特性，以评估含 DHA 的特定 MCT:n-3 TGRP 介导的膜结构和活性的变化、EPA 或两者兼而有之。在目标 2 中，我们将定义负责在培养的免疫效应巨噬细胞和小鼠模型中目标 1 中表征的特定 MCT:n-3 TGRP 的内化和代谢利用的细胞摄取途径。然后，我们将在目标 3 下研究 MCT:n-3 TGRP 细胞内化如何影响单核细胞和巨噬细胞响应小鼠模型中的急性免疫刺激 (LPS) 的功能活动。拟议的细胞和动物模型研究将建立创新方法，适用于将亲脂性和疏水性治疗剂靶向、快速递送到特定器官或组织。我们将揭示 MCT 和 n-3 TG 之间调节膜脂组成、细胞脂代谢和免疫反应的新协同作用。我们的研究将对许多领域具有重要意义，包括对感染的免疫反应以及炎症相关的组织损伤和器官功能障碍。