Abstract 227: The Role of Fatty Acid Desaturase 1 in Inflammation Initiation and Resolution in Atherosclerosis

Abstract

Studies suggest that dietary enrichment of polyunsaturated fatty acids (PUFAs) may improve CVD outcomes, however the mechanisms underlying these observations remain elusive. Additionally, genome-wide association studies have linked single nucleotide polymorphisms (SNPs) in genes encoding essential PUFA metabolizing enzymes, the Fatty Acid Desaturases 1, 2, and 3 ( FADS1-2-3 ), to dyslipidemia and other metabolic risk factors known to be linked to CVD. Since enzymatic oxidation of specific PUFAs, commonly arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), generate signaling mediators that coordinate both the initiation and resolution of inflammation, understanding the interplay of PUFA metabolism and vascular inflammation has broad implications in cardiometabolic drug discovery. Here we have altered the abundances of distinct dietary and endogenously-synthesized PUFAs, and associated lipid mediators, in hyperlipidemic Ldlr-/- mice to understand the signaling mechanisms underlying the PUFA-CVD link. We diversified PUFA profiles by feeding diets enriched in either ω-6 or ω-3 PUFAs, and inhibited endogenous production of AA and EPA by antisense oligonucleotide (ASO)-mediated knockdown of the Δ5 desaturase Fads1. Fads1 knockdown results in accumulation of its substrate fatty acids (dihomo-γ-linolenic acid and eicosatrienoic acid) and marked reduction in its enzymatic products (AA and EPA). Metabololipidomic profiling reveals that Fads1 knockdown alters select AA-, EPA-, and DHA-derived lipid mediators in a diet-specific manner. Interestingly, Fads1 knockdown protects Ldlr-/- mice from obesity and insulin resistance regardless of diet, yet alters increases circulating monocyte subsets and promotes dyslipidemia in a highly diet-specific manner. How these phenotypes link to diet-induced atherosclerosis burden in Fads1 knockdown mice will also be presented. Collectively, our studies provide new information in regards to the relative contribution of endogenous (FADS1-derived) and exogenous (diet-derived) AA and EPA in driving cardiometabolic phenotypes. Furthermore, our studies provide the first mechanistic understanding behind the genetic link of FADS1-2-3 SNPs and atherosclerosis.