Desaturase and elongase-limiting endogenous long-chain polyunsaturated fatty acid biosynthesis

Abstract

Purpose of review: Endogenous synthesis of the long-chain polyunsaturated fatty acids (LCPUFAs) is mediated by the fatty acid desaturase (FADS) gene cluster (11q12-13.1) and elongation of very long-chain fatty acids 2 (ELOVL2) (6p24.2) and ELOVL5 (6p12.1). Although older biochemical work identified the product of one gene, FADS2, rate limiting for LCPUFA synthesis, recent studies suggest that polymorphisms in any of these genes can limit accumulation of product LCPUFA.

Recent findings: Genome-wide association study (GWAS) of Greenland Inuit shows strong adaptation signals within FADS gene cluster, attributed to high omega-3 fatty acid intake, while GWAS found ELOVL2 associated with sleep duration, age and DNA methylation. ELOVL5 coding mutations cause spinocerebellar ataxia 38, and epigenetic marks were associated with depression and suicide risk. Two sterol response element binding sites were found on ELOVL5, a SREBP-1c target gene. Minor allele carriers of a 3 single nucleotide polymorphism (SNP) haplotype in ELOVL2 have decreased 22 : 6n-3 levels. Unequivocal molecular evidence shows mammalian FADS2 catalyzes direct Δ4-desaturation to yield 22 : 6n-3 and 22 : 5n-6. An SNP near FADS1 influences the levels of 5-lipoxygenase products and epigenetic alteration.

Summary: Genetic polymorphisms within FADS and ELOVL can limit LCPUFA product accumulation at any step of the biosynthetic pathway.

Figure 1

LCPUFA Biosynthesis Pathway. The omega 6 (n-6) and omega 3 (n-3) fatty acids are substrates in competition for the same sets of FADS and ELOVL catalyzing desaturation and elongation, respectively. Elongation is mediated by a four enzyme coupled system; the first, rate limiting enzyme is the “elongase”.

Figure 2

Biosynthesis of monounsaturated fatty acids (MUFA) in mouse and human skin. Human skin expresses only FADS2 while mice and all other animals’ skin expresses only Scd1. Both SCD1 and FADS2 are expressed and their resulting enzymes are active in liver and other organs of both humans and mice. Mouse: Scd1 mediates 18:0 conversion to 18:1n-9 and 16:0 conversion to 16:1n-7; Human: FADS2 mediates conversion of 16:0 to 16:1n-10 but has no effect on any other saturated fatty acid (e.g. 18:0 no enzymatic activity).