Abstract 4128491: Dietary N-3 Very-Long-Chain Polyunsaturated Fatty Acids Improve Retinal Function And Reduce Aortic Atherosclerosis In ApoE-Deficient Mice

Introduction: N-3 very-long-chain polyunsaturated fatty acids (VLCPUFA; C≥24), which are found primarily in retina and a few other select tissues, are known to play critical roles in specific biological systems. Although n-3 PUFA, such as eicosapentanoic acid (EPA, C20:5 n-3) and docosahexaenoic acid (DHA, C22:6 n-3), may confer cardiovascular benefits, they did not improve age-related macular degeneration (AMD), a leading cause of blindness worldwide, in clinical trials. The activity of ELOVL fatty acid elongase 2 (ELOVL2), an enzyme that converts EPA into tetracosapentaenoic acid (TPA, C24:5 n-3), is known to decrease in the retina with age due to promoter methylation. Hypothesis: We hypothesized that dietary VLCPUFA may delay or prevent AMD, by bypassing the ELOVL2-mediated lipid elongation step. We also hypothesize that VLCPUFA may benefit cardiometabolic health like shorter-chain n-3 PUFA through similar mechanisms. Aims: We aimed to investigate the effect of dietary VLCPUFA on retinal function and cardiometabolic risk factors in mice. Methods: We have produced a new fish oil that contains ~40% (w/w) of C24-C28-rich VLCPUFA. We fed 9-month-old ApoE -/- mice with normal or VLCPUFA fortified diet (1% or 3% (w/w)) for 8 weeks, and age-matched C57BL/6J mice were used as control. We conducted electroretinography (ERG) and cognitive ability tests at the end of feeding period. In in vitro studies, we performed PPAR reporter assay and investigated the anti-inflammatory effects of TPA in lipopolysaccharide-stimulated RAW264.7 cells. Results: Supplementation of VLCPUFA showed a significant and dose-dependent improvement in ERG response. Like EPA and DHA, we also observed favorable cardiometabolic changes and decreased atherosclerotic plaque area due to dietary VLCPUFA. Intriguingly, VLCPUFA supplemented aging mice exhibit better cognitive performance compared with control. Transcriptome analysis revealed that VLCPUFA-enriched fish oil favorably regulated genes involved in nuclear receptor signaling pathways, lipid metabolism and inflammation. Furthermore, purified TPA potently activates PPARs, and suppressed inflammation in macrophage cells. Conclusions: Overall, our studies revealed for the first time several potential health benefits for our new VLCPUFA-enriched fish oil in several age-related diseases and support its future development as a new dietary supplement.