New understandings of the pathway of long-chain polyunsaturated fatty acid biosynthesis

Abstract

Purpose of review Molecular studies have clarified the roles of the fatty acid desaturase (FADSx) and elongation of very long chain fatty acid (ELOVLx) genes, as well as acyl-coenzyme A synthase long-chain isoforms (ACSLx) required for entry to long-chain polyunsaturated fatty acid (LCPUFA) biosynthetic pathways. Recent findings FADS1 and FADS2 but not FADS3 are active toward PUFA. FADS1 is a Δ5-desaturase operating on five C20 PUFA, and is strongly regulated by human genetic polymorphisms, modulating circulating arachidonic acid (20:4n-6) levels. In contrast, FADS2 operates on at least 16 substrates, including five saturates, and catalyzes Δ6, Δ4, and Δ8 desaturation. FADS2 silencing in cancer cells leads to FADS1 synthesis of unusual fatty acids. ACSL6 and ACSL4 are required to maintain tissue 22:6n-3 and 20:4n-6, respectively. FADS2AT2, is the first transcript to differentially inhibit desaturation, attenuating 18:3n-3 but not 18:2n-6 desaturation. The PUFA elongases ELOVL5, 2, and 4 are implicated in cancer, age-related methylation, and retinal degeneration, respectively. Summary The mixture of fatty acids available to FADS2 in any tissue defines the product mixture available for further synthesis of membrane lipids and signaling molecules and may be relevant in many clinical conditions including cancer. Functional genetic variants define the levels of circulating arachidonic acid via FADS1 regulation; genotypes that drive high arachidonic acid may predispose to disease.

Polyunsaturated fatty acids and fatty acid-derived lipid mediators: Recent advances in the understanding of their biosynthesis, structures, and functions

“…In this way we could be confident that findings of no activity in one enzyme vs. activity in the other was reflective of differential specificity. We have also discovered functions of alternatively spliced (nonclassical transcripts), beyond the scope of this brief review [ 30 ].…”

Fifty-one novel and replicated GWAS loci for polyunsaturated and monounsaturated fatty acids in 124,024 Europeans

“…One novel locus at chr10q23 has a cluster of genes in the cytochrome P450 superfamily (i.e., The two key sets of genes which catalyze LCPUFA biosynthesis are fatty acid desaturase (FADS) and elongase protein family genes (ELOVL) [7]. We have re-confirmed the primary importance of FADS genes in n-3 LCPUFA genetics, as these genes had the most significant Pvalues in our meta-analysis at lead SNPs rs174528 (DHA, P < 1E-300; MAF = 0.39) and rs509360 (omega-3, P < 1E-300; MAF =0.33).…”

“…Omega-3 long-chain PUFAs (n-3 LCPUFAs) have been consistently shown to improve aspects of metabolic syndrome that are related to cardiovascular disease and obesity-related risk factors such as insulin resistance, hypertension, and dyslipidemia [1, 4, 5], while omega-6 (n-6) LCPUFAs have been associated with both positive and negative health outcomes [6]. Excess n-6 linoleic acid (LA) suppresses tissue and circulating n-3 LCPUFAs, due to common enzymes operating on both PUFA families; balance in dietary n-6 and n-3 is necessary to avoid suppression of the functional n-3 LCPUFAs, EPA and DHA [7]. Modest overall dietary PUFAs and an n-6/n-3 ratio up to 4/1 have been recommended, while the typical industrialized diet has a ratio of 15/1 or more [8, 9].…”

“…Omega-6 (n-6) LCPUFAs have been associated with both positive and negative health outcomes 6 . Excess n-6 linoleic acid (LA) suppresses tissue and circulating n-3 LCPUFAs, due to common enzymes operating on both PUFA families; balance in dietary n-6 and n-3 is necessary to avoid suppression of the functional n-3 LCPUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) 7 . Modest overall dietary PUFAs and an n-6/n-3 ratio up to 4/1 have been recommended, while the typical modern industrialized diet has a ratio approximating 15/1 8,9 .…”

FADS2 Function at the Major Cancer Hotspot 11q13 Locus Alters Fatty Acid Metabolism in Cancer

“…(48,49), 137 bp downstream of a sterol response element in FADS2 intron 1 (47). Polymorphism status controlling the FADS1-meditated step 20:3→20:4 (AA) also causes all upstream precursors to be depleted and downstream products to be enriched, fully consistent with FADS1 as the pivotal control point in HUFA biosynthesis (39). The FADS1 expression is significantly increased in several primary tumors and even at a higher level in the metastatic and recurrent tumors (50).…”