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.

Arachidonic acid (AA) is the major polyunsaturated fatty acid (PUFA) substrate for potent eicosanoid signaling to modulate inflammation and thrombosis and is controlled in part by tissue abundance. Fatty acid desaturase 1 (FADS1) catalyzes synthesis of omega-6 (n-3) AA and n-3 eicosapentaenoic acid (EPA). The rs66698963 polymorphism, a 22-base pair (bp) insertion-deletion 137 bp downstream of a sterol regulatory element in FADS2 intron 1, mediates expression of FADS1 in vitro, as well as exerting positive selection in several human populations. The associations between the polymorphism rs66698963 and plasma PUFAs as well as disease phenotypes are unclear. This study aimed to evaluate the relation between rs66698963 genotypes and plasma PUFA concentrations and blood lipid profiles. Plasma fatty acids were measured from a single sample obtained at baseline in 1504 healthy Chinese adults aged between 35 and 59 y with the use of gas chromatography. Blood lipids were measured at baseline and a second time at the 18-mo follow-up. The rs66698963 genotype was determined by using agarose gel electrophoresis. Linear regression and logistic regression analyses were performed to assess the association between genotype and plasma PUFAs and blood lipids. A shift from the precursors linoleic acid and α-linolenic acid to produce AA and EPA, respectively, was observed, consistent with FADS1 activity increasing in the order of genotypes D/D to I/D to I/I. For I/I compared with D/D carriers, plasma concentrations of n-6 AA and the ratio of AA to n-3 EPA plus docosahexaenoic acid (DHA) were 57% and 32% higher, respectively. Carriers of the deletion (D) allele of rs66698963 tended to have higher triglycerides (β = 0.018; SE: 0.009; P = 0.05) and lower HDL cholesterol (β = -0.008; SE: 0.004; P = 0.02) than carriers of the insertion (I) allele. The rs66698963 genotype is significantly associated with AA concentrations and AA to EPA+DHA ratio, reflecting basal risk of inflammatory and related chronic disease phenotypes, and is correlated with the risk of dyslipidemia. This trial was registered at chictr.org.cn as ChiCTR-EOC-17012759.

Normal odd-chain SFA (OCSFA), particularly tridecanoic acid (n-13 : 0), pentadecanoic acid (n-15 : 0) and heptadecanoic acid (n-17 : 0), are normal components of dairy products, beef and seafood. The ratio ofn-15 : 0:n-17 : 0 in ruminant foods (dairy products and beef) is 2:1, while in seafood and human tissues it is 1:2, and their appearance in plasma is often used as a marker for ruminant fat intake. Human elongases encoded by elongation of very long-chain fatty acid (ELOVL)1, ELOVL3, ELOVL6 and ELOVL7 catalyse biosynthesis of the dominant even-chain SFA; however, there are no reports of elongase function on OCSFA. ELOVL transfected MCF7 cells were treated withn-13 : 0,n-15 : 0 orn-17 : 0 (80 µm) and products analysed. ELOVL6 catalysed elongation ofn-13 : 0→n-15 : 0 andn-15 : 0→n-17 : 0; and ELOVL7 had modest activity towardn-15 : 0 (n-15 : 0→n-17 : 0). No elongation activity was detected forn-17 : 0→n-19 : 0. Our data expand ELOVL specificity to OCSFA, providing the first molecular evidence demonstrating ELOVL6 as the major elongase acting on OCSFAn-13 : 0 andn-15 : 0 fatty acids. Studies of food intake relying on OCSFA as a biomarker should consider endogenous human metabolism when relying on OCSFA ratios to indicate specific food intake.