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

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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.