Exploring the Synergistic Action of Medium-Chain Triglycerides and Omega-3 Fatty Acids to Enhance Cellular Uptake and Anti-Inflammatory Responses

<i>Objectives:</i> Omega-3 fatty acids (<i>n</i>-3 FA) exhibit pro-healing and anti-inflammatory properties. Injectable lipid emulsions containing <i>n</i>-3 FA are being explored for the treatment of acute adverse conditions. Our previous studies demonstrated that a triglyceride (TG)-rich emulsion (TGRP) containing medium-chain TG (MCT) and <i>n</i>-3 TG (8:2 ratio) is rapidly cleared from the blood and efficiently taken up by organs. This study systematically examined the impact of varying MCT:<i>n</i>-3 ratios on cellular uptake and metabolic function in inflammatory processes. <i>Methods and results:</i> We measured the uptake of radio-labeled TGRP, comprising pure MCT, <i>n</i>-3, or mixed at selected ratios (8:2, 6:4, 2:8), both in vitro and in vivo. Murine macrophages with MCT:<i>n</i>-3 (6:4 or 2:8) had a 2-fold higher TG uptake. IV-injected mixed TGRP also enhanced blood clearance and organ uptake. <i>n</i>-3 TGRP reduced LPS-induced pro-inflammatory cytokines (TNF-α, IL-1, IL-6) in a dose-dependent manner. The 8:2 ratio enhanced mitochondrial respiration and glycolytic capacity in macrophages. Pro-inflammatory lipids decreased with MCT:<i>n</i>-3 (2:8) and pure <i>n</i>-3 TGRP. Bolus injections of <i>n</i>-3 TGRP with MCT lowered LPS-induced IL-6 in plasma and tissues. <i>Conclusions:</i> MCT and <i>n</i>-3 FA support metabolic activity and exhibit anti-inflammatory effects, suggesting that optimizing their ratio may enhance the therapeutic effects of emulsions for inflammatory conditions.