Identification of phenotypic lipidomic signatures in response to long chain n-3 polyunsaturated fatty acid supplementation in humans

Authors: Picklo, Matthew; VALLEE MARCOTTE, BASTIEN - University Of Laval; Bukowski, Michael; Rust, Bret; GUENARD, FREDERIC - University Of Laval; VOHL, MARIE-CLAUDE - University Of Laval

Submitted to: Journal of the American Heart Association
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/30/2020
Publication Date: 1/19/2021
Citation: Picklo, M.J., Vallee Marcotte, B., Bukowski, M.R., Rust, B.M., Guenard, F., Vohl, M. 2021. Identification of phenotypic lipidomic signatures in response to long chain n-3 polyunsaturated fatty acid supplementation in humans. Journal of the American Heart Association. 10. Article 18126. https://doi.org/10.1161/JAHA.120.018126.
DOI: https://doi.org/10.1161/JAHA.120.018126

Interpretive Summary: Low blood lipids are associated with a lower risk of cardiovascular disease (CVD). Intake of dietary long chain omega-3/n-3 (LCn-3) polyunsaturated fatty acids like those found in fish oil is used for reducing blood triglyceride (TG) concentrations. However, interindividual variability exists in that some people (about 30%) do not respond to LCn-3 intake or even have elevations in blood TG after LCn-3 intake. In this work, using blood samples from an LCn-3 intake study, we determined the concentrations of specific TG and cholesterol (Chol) molecules in people that respond to LCn-3 supplementation with decreases in TAG and in people that have increases in TG. Our data demonstrate that concentrations of some TG, but not others, are reduced in people who respond to LCn-3 intake and that these same TG molecules increase in people who have elevations in TG. We also show that blood Chol molecules are reduced in a small portion of people that have a reduction in TG. Importantly, we also show that increases in blood Chol molecules happen in a majority of people who have increases in blood TG after LCn-3 intake. This research provides greater insight into the prevention of CVD by LCn-3 intake by identifying the basis for why some people may benefit from LCn-3 intake and why other people may not. These findings have great value for clinicians, nutritionists, and research scientists.

Technical Abstract: Background: Background: Supplementation with long chain n-3 polyunsaturated fatty acids (LCn-3; PUFA) is used to reduce total circulating triacylglycerol (TAG) concentrations. However, in about 30% of people, supplementation with LCn-3; PUFA does not result in decreased plasma TAG. Lipidomic analysis may provide insight into this inter-individual variability. Methods: Lipidomic analyses using targeted, mass spectrometry (MS) were performed on plasma samples obtained from a clinical study in which participants were supplemented with 3 g/day of LCn-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 three potential responder phenotypes: (1) positive responder (Rpos; TAG decrease), (2) non-responder (Rnon; lacking TAG change), and (3) negative responder (Rneg; TAG increase) representing 67%, 18%, and 15% of the study participants, respectively. Results: Separation of the three phenotypes was attributed to differential responses in TAG with 50-54 carbons with 1-4 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 Rpos phenotype vs the Rneg phenotype with intermediate responses in the Rnon phenotype. CE 20:5, containing eicosapentaenoic acid (20:5n-3), was elevated in all phenotypes. Conclusion: These data identify lipidomic signatures, TAG and CE, associated with LCn-3 response phenotypes and identify a novel phenotype based upon CE changes. Clinical Trial Registration: This trial was registered at www.clinicaltrials.gov as NCT01343342