Identification of Phenotypic Lipidomic Signatures in Response to Long Chain n‐3 Polyunsaturated Fatty Acid Supplementation in Humans

BACKGROUND: Supplementation with long chain n‐3 polyunsaturated fatty acids is used to reduce total circulating triacylglycerol (TAG) concentrations. However, in about 30% of people, supplementation with long chain n‐3 polyunsaturated fatty acids does not result in decreased plasma TAG. Lipidomic analysis may provide insight into this inter‐individual variability. METHODS: Lipidomic analyses using targeted, mass spectrometry were performed on plasma samples obtained from a clinical study in which participants were supplemented with 3 g/day of long chain n‐3 in the form of fish oil capsules over a 6‐week period. TAG species and cholesteryl esters (CE) were quantified for 130 participants pre‐ and post‐supplementation. Participants were segregated into 3 potential responder phenotypes: (1) positive responder (R(pos); TAG decrease), (2) non‐responder (R(non); lacking TAG change), and (3) negative responder (R(neg); TAG increase) representing 67%, 18%, and 15% of the study participants, respectively. Separation of the 3 phenotypes was attributed to differential responses in TAG with 50 to 54 carbons with 1 to 4 desaturations. Elevated TAG with higher carbon number and desaturation were common to all phenotypes following supplementation. Using the TAG responder phenotype for grouping, decreases in total CE and specific CE occurred in the R(pos) phenotype versus the R(neg) phenotype with intermediate responses in the R(non) phenotype. CE 20:5, containing eicosapentaenoic acid (20:5n‐3), was elevated in all phenotypes. A classifier combining lipidomic and genomic features was built to discriminate triacylglycerol response phenotypes and reached a high predictive performance with a balanced accuracy of 75%. CONCLUSIONS: These data identify lipidomic signatures, TAG and CE, associated with long chain n‐3 response p henotypes and identify a novel phenotype based upon CE changes. REGISTRATION: URL: https://www.ClinicalTrials.gov; Unique Identifier: NCT01343342.