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: 10538572
• 负责人: Chuchun Liz Chang
• 金额: $ 38.59万
• 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/10538572
• 关键词: Acceleration; 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; Cerebral Ischemia; Chronic; Clinical; Coupled; Data; Dimensions; Disease; Docosahexaenoic Acids; Eicosanoids; Eicosapentaenoic Acid; Emulsions; Endothelial Cells; Experimental Animal Model; Fatty Acids; Fish Oils; Fishes; 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; Macrophage; 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; Parenteral Nutrition; Pathway interactions; Phospholipids; Physical Chemistry; Physiological; Plasma; Prevention; Production; Property; Regulation; Reporting; Research; Resolution; Route; Series; Spinal cord injury; Stimulus; System; TNF gene; Therapeutic; Therapeutic Agents; Tissues; Triglyceride Metabolism; Triglycerides; acute infection; advanced analytics; biophysical properties; biophysical techniques; design; experimental study; fatty acid oxidation; healing; human model; in vivo; innovation; intravenous injection; lipid disorder; lipid metabolism; lipidomics; lipophilicity; 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。 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膜富集。 N-3脂肪酸（FA）越来越多地被认为是静脉注射中的一种有效补充剂，因为它们对凋亡以及自由基的产生和产生自由基和促炎性类类类药物的产生。实验动物模型中的研究表明，注射N-3 TG-富乳液颗粒（TGRP）的推注在降低中风后脑死亡和发病率方面具有治疗性保护性。我们发现，与其他TGRP相比，含有MCT和鱼油TG（8：2 wt/wt）的TGP（8：2 wt/wt）富含N-3 FA的细胞膜和内皮细胞的效率更高。使用核磁共振（NMR），我们报告说，将MCT纳入模型TGRP会促进模型膜脂质疾病，该模型可能会加速N-3递送速率，从而强调了向N-3 FA富集的Bolus注射的优势。但是，很少有研究解决了急性IV N-3给药的急性抗炎作用。当前，尚无关于MCT与N-3 TG的最佳混合物的数据，可以实现最快，最高的抗炎作用。我们的中心假设是，对含有MCT和N-3 TG的TGRP的注射大量将对膜动力学进行协同影响，以加速N-3 FA掺入细胞膜，这将启动N-3介导的抗炎和抗源自作用。这些将根据3个特定目标进行研究。在AIM 1下，我们将使用不同的N-3 TG含量的含MCT的TGRP的生物物理特性，使用生物物理方法与基于质谱的脂质组学结合，以评估由特定MCT介导的膜结构的改变和活性的变化：N-3 TGRP含有DHA，EPA或两者。在AIM 2中，我们将定义负责特定MCT内部化和代谢利用的细胞摄取途径：N-3 TGRP在培养的免疫效应巨噬细胞和小鼠模型中在AIM 1中表征的N-3 TGRP。然后，我们将在AIM 3下研究MCT：N-3 TGRP细胞内在化如何影响小鼠模型中急性免疫刺激（LPS）的单核细胞和巨噬细胞的功能活性。在细胞和动物模型中提出的研究将建立创新的方法，这些方法可适应于靶向，快速递送亲脂性和疏水性治疗剂到特定器官或组织。我们将发现MCT和N-3 TG之间的新型协同作用，以调节膜脂质组成，细胞脂质代谢和免疫反应。我们的研究对许多领域具有很高的意义，包括对感染和炎症相关的组织损伤和器官功能障碍的免疫反应。