Knockdown of Δ-5 Fatty Acid Desaturase Is More Than Just a Fad.

Abstract

Human genome-wide association studies have revealed a large number of genomic loci linked to cardiometabolic disease traits.1–3 However, for many of the gene variants identified, it remains unknown how they functionally influence the disease phenotype or whether these genes represent new therapeutic targets. Single-nucleotide polymorphisms in FADS1 , which encodes Δ-5 fatty acid desaturase, have been identified in many large genome-wide association studies as strongly linked to cardiometabolic diseases including obesity, type 2 diabetes mellitus, dyslipidemia, fatty liver, liver enzyme elevation, and coronary artery disease.1–9 The underlying mechanisms by which variants of FADS1 link to these phenotypes is unknown. FADS1 is the only mammalian Δ-5 fatty acid desaturase enzyme capable of introducing a double bond at carbon 5 (from the carboxyl group) leading to the synthesis of the critically important polyunsaturated fatty acids arachidonic acid (AA) and eicosapentaenoic acid (EPA) from dihomo-γ-linolenic acid (20:3, ω-6) and eicosatetraenoic acid (20:4, ω-3), respectively (Figure).10 Figure. The knockdown of Δ-5 fatty acid desaturase Fads1 impacts metabolic disease parameters by altering the balance of proinflammatory and proresolving lipid mediators in a diet-specific manner. A , Enzymes and fatty acids that comprise the ω-6 and ω-3 fatty acid pathways leading to the synthesis of proinflammatory and proresolving lipid mediators. The murine fatty acid desaturase 1 gene ( Fads1 ) encodes the enzyme Δ-5 fatty acid desaturase and catalyzes the conversion of dihomo-γ-linolenic acid (DGLA, 20:3, ω-6) or eicosatetraenoic acid (ETA, 20:4, ω-3) to arachidonic acid (AA, 20:4, ω-6) or eicosapentaenoic acid (EPA, 20:5, ω-3), respectively. B , The impact of Fads1 knockdown by antisense oligonucleotides (ASO) in Ldlr −/− mice fed diets enriched in ω-6 AA precursors ( left ) or diets enriched in ω-3 EPA precursors ( right ). Inflammation, mRNA expression, metabolic parameters, inflammatory markers, and atherosclerosis were assessed primarily in liver, …