Abstract 462: Dose Matters: Omega-3 Polyunsaturated Fatty Acid Supplementation at 3600 mg/d but Not 900 mg/d Reduces Inflammatory Response to Evoked Endotoxemia in Healthy Volunteers

Abstract

Inflammation is a key component in the pathogenesis of cardiometabolic disease. Certain anti-inflammatory compounds may improve atherosclerotic disease risk by modulating systemic and vascular inflammation. Long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) may represent a dietary mechanism for improving cardiometabolic health through reduction of inflammation. We hypothesized that n-3 PUFA supplementation would reduce the inflammatory response to evoked endotoxemia in healthy humans. In the Fenofibrate and omega-3 Fatty Acid Modulation of Endotoxemia study (FFAME Study), we recruited healthy individuals (N=60; age 18-45; BMI 18-30; 43% Female; 65% Caucasian, 20% African, 15% Asian ancestry) randomized to one of three treatment groups; n-3 PUFA (Lovaza 465mg EPA/375mg DHA) supplemented at either 900mg per day or 3,600mg per day, or placebo. An additional arm of the study included a fenofibrate treatment group, not included here. Participants were treated for ∼8 weeks then admitted to the research center for an endotoxin challenge of lipopolysaccharide (LPS) 0.6ng/kg intravenously. Multiple clinical and biochemical variables were assessed throughout, and analyzed using RM-ANOVA with Bonferroni post-hoc tests for between group differences. Compared to placebo, high-dose (P<0.01) but not low dose n-3 PUFA reduced peak temperature, but not heart rate or blood pressure, responses to endotoxin. Cytokines and inflammatory markers (IL-6, TNFα, IL-10, CRP, SAA) were decreased in high-dose n-3 PUFA vs. placebo . Interestingly, these inflammatory markers tended to be increased in low-dose n-3 PUFA vs. placebo, with a significant difference in the effect of low-dose vs. high-dose n-3 PUFA on peak IL-6 (P<0.001), TNFα (P<0.01) and IL-10 (P<0.05). Plasma lipids tended to decrease in both n-3 PUFA groups compared with placebo, with equal lipid-lowering effect of 900 or 3,600 mg/day on cholesterol, ApoA-I, and triglycerides. The specific anti-inflammatory properties of n-3 PUFA appear to be dose-specific, with high doses (3,600mg/day) leading to attenuation of the inflammatory response to evoked endotoxemia, while lower doses (900mg/day) do not reduce the inflammatory response despite similar reductions in plasma lipids.