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Title:   Author  item
                                            Newman, Johnitem
                                            Pedersen, Theresaitem
                                            BRANDENBURG, VERDAYNE - Sanford And Burnham Medical Research Instituteitem
                                            HARRIS, WILLIAM - Sanford And Burnham Medical Research Instituteitem
                                            SHEARER, GREGORY - University Of South Dakota
  Submitted to: PLOS ONE
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 10/3/2014
                                    Publication  Date: 10/3/2014
                                    Citation: Newman, J.W., Pedersen, T.L., Brandenburg, V.R., Harris, W.S., Shearer, G.C. 2014. Effect of omega-3 fatty acids on the oxylipin composition of lipoproteins in hypertriglyceridemic, statin-treated subjects. PLoS One. 9(11):e111471. doi: 10.1371/journal.pone.0111471.Interpretive Summary: The human body produces lipid mediators of inflammation and vascular function when and where required.  However, many of these same compounds occur within lipid transport particles in the bloodstream.  The bioactive lipids within these lipid-rich particles may affect inflammation and vascular health.  For instance, the positive health effects noted for omega-3 fatty acid rich foods may result from an increase in the anti-inflammatory metabolites of these lipids within circulating lipid rich particles.  To investigate this possibility, we asked whether lipoprotein-associated lipid mediators in subjects achieving optimal LDL-cholesterol are characteristic of inflammatory stress despite statin therapy, and if so, do omega-3 fatty acids alter the mediator composition in a manner consistent with reduced inflammation and improved vascular function.  To this end, 15 subjects with controlled LDL-cholesterol were treated with 4 g/d omega-3 acid ethyl esters (P-OM3) for 8 weeks.  Lipid mediators derived from both omega-6 and omega-3 fatty acids were measured within HDL, LDL, and VLDL at baselines and at their final visits.  Omega-6 mediators were the most abundant species measured in plasma at baseline and had their particle relative abundance decreased in the order of HDL > VLDL > LDL, with 42%, 27% and 21%, respectively.  Omega-3 metabolites combined constituted less than 11% of baseline oxylipins.  While HDL primarily carried alcohols and epoxides, VLDL was also rich in ketones.  P-OM3 treatment uniformly decreased AA-mediators across lipoproteins by 23% (p=0.0003), and expanded EPA-mediators by 322%, (p<0.0001) and DHA-derived pools by 123% (p<0.0001). Finally, in this study we found that each lipoprotein fraction carries a unique oxylipin complement.  P-OM3 treatment alters lipoprotein-oxylipins, reducing pro-inflammatory and increasing anti-inflammatory species, consistent with reduced inflammatory stress and improved vascular activities associated with this treatment. While descriptive in nature, this study indicates that dietary omega-3 fatty acids alter the bioactive lipid composition of circulating lipid particles in a manner consistent with a vascular health benefit.  Future studies should specifically assess the biological activity of these modified particles.
                                Technical Abstract: Background: Oxylipins mediate many physiological processes, including inflammation and vascular function.  Generally considered local and transient, we suggest their presence in lipoproteins indicates they also mediate the effects lipoproteins have on inflammation and vascular biology. To support this, we asked whether lipoprotein oxylipins in subjects achieving optimal LDL-cholesterol are characteristic of inflammatory stress despite statin therapy, and if so, do omega-3 fatty acids alter oxylipin composition in a manner consistent with reduced inflammation and improved vascular function.

Methods:  Subjects (n=15) with optimally controlled LDL-cholesterol were treated with 4 g/d omega-3 acid ethyl esters (P-OM3) for 8 weeks to alter their oxylipin substrate pools.  Oxylipins derived from arachidonate, eicosapentaenoate (EPA), and docosahexaenoate (DHA) within HDL, LDL, and VLDL were measured at baseline and final visits.  These included mid-chain alcohols (HETEs, HEPEs and HDoHEs), ketones (KETEs), epoxides (as EpETrEs –commonly EETs– EpETEs, and EpDPEs), and select other oxylipins.  

Results:  Arachidonate-oxylipins (HETEs, KETEs, and EpETrEs) were the most abundant species measured in plasma at baseline.  They also had the greatest relative abundance ([95% CI]) in HDL 42% [31, 57] followed by VLDL 27% [20, 36], and LDL 21% [16, 28].  EPA- and DHA-oxylipins combined constituted less than 11% of baseline oxylipins.  While HDL primarily carried alcohols and epoxides, VLDL was also rich in ketones.  P-OM3 treatment uniformly decreased AA-oxylipins across lipoproteins by 23% [33, 12], p=0.0003, and expanded EPA-oxylipins by 322% [241, 422], p<0.0001 and DHA pools by 123% [80, 176], p<0.0001.

Conclusions:  Each lipoprotein fraction carries a unique oxylipin complement.  P-OM3 treatment alters lipoprotein-oxylipins, reducing pro-inflammatory (i.e.VLDL-HETEs) and increasing anti-inflammatory species (i.e. VLDL-EpETEs), consistent with reduced inflammatory stress and improved vascular activities associated with this treatment.


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