Disease relevance of FADS2

• The human isoform 2 of FADS (hFADS2), which is the product of FLAD1 gene, was over-expressed in Escherichia coli as a T7-tagged protein and identified by MALDI-TOF MS analysis [1].
• The predictive value of D5D activity was independent of lifestyle factors (smoking, BMI and physical activity), whereas the risk associated with higher SCD-1 and D6D activities was mainly explained by obesity [2].
• We observed a significant decrease in D6D activity, evaluated by a radiochemical technique using 1-[14C]-linoleic acid as substrate, in cirrhotic patients with no correlation with the etiology of the cirrhosis [3].

High impact information on FADS2

• A nucleotide insertion in the transcriptional regulatory region of FADS2 gives rise to human fatty acid delta-6-desaturase deficiency [4].
• Within human skin, Delta-6 desaturase/FADS2 mRNA and protein expression is restricted to differentiating sebocytes located in the suprabasal layers of the sebaceous gland [5].
• We investigated the molecular mechanism of FADS2 deficiency in skin fibroblasts from a patient deficient in this enzyme [4].
• Delta-6 desaturase, also known as fatty acid desaturase-2 (FADS2), is a component of a lipid metabolic pathway that converts the essential fatty acids linoleate and alpha-linolenate into long-chain polyunsaturated fatty acids [5].
• The hepatic expression of D5D as well as Delta(6)-desaturase (D6D) was highly activated in transgenic mice overexpressing nuclear SREBP-1a, -1c, and -2 [6].

Biological context of FADS2

• A key regulator of desaturase gene expression is sterol-regulatory element binding protein-1c (SREBP-1c), which mediates transcriptional activation of the SCD and D6D genes by insulin and inhibition by HUFAs [7].
• Two different fad2 cDNAs from an embryo cDNA library map to separate chromosomal positions, providing evidence consistent with two different isoforms of fad2 expressed in the embryo [8].
• The fad2 cDNAs from multiple tissue sources clustered into three groups on a phenogram, and map to different positions on chromosomes 4, 5 and 10, which suggests at least three different isoforms of fad2 may be expressed in the maize plant [8].
• Genospecies 14 (Bouvet) yielded a very weak cross-reaction with genospecies 3 serovar 20, and genospecies TU 13 reacted weakly with anti-genospecies 3 serovar 15 serum [9].

Anatomical context of FADS2

• Despite these different physiological roles of SCD and D6D/D5D, these desaturases share common regulatory features, including dependence of expression on insulin, suppression by HUFAs, and induction by peroxisome proliferators (PPs) [7].
• Following the cloning of mammalian Delta6-desaturase (D6D), the D6D mRNA was found in many tissues, including adult brain, maternal organs, and fetal tissue, suggesting an active synthesis of HUFA in these tissues [10].
• The delta-6-desaturase (D6D) activity was evaluated in microsomes from liver fragments of cholecystectomized subjects without any liver pathology and from explanted liver of patients affected by cirrhosis of different etiologies [3].
• CONCLUSION: We found a decreased level of arachidonic acid in breast milk in atopic compared to non-atopic mothers, but no indication that the rate-limiting enzymatic step (D6D) is involved [11].
• Delta-6-desaturase (D6D) levels have been found to fall rapidly in the testes and more slowly in the liver in aging rats [12].

Associations of FADS2 with chemical compounds

• The expressed protein accounted for more than 40% of the total protein extracted from the cell culture; 10% of it was recovered in a soluble and nearly pure form by Triton X-100 treatment of the insoluble cell fraction. hFADS2 possesses FADS activity and has a strict requirement for MgCl(2), as demonstrated in a spectrophotometric assay [1].
• Delta-6 Desaturase (D6D) and Delta-5 desaturase (D5D) are the key enzymes for the synthesis of highly unsaturated fatty acids (HUFAs), such as arachidonic acid (20:4, n -6) and docosahexaenoic acid (22:6, n -3), that are incorporated in phospholipids (PLs) and perform essential physiological functions [7].
• The maize fad2 cDNAs showed an amino-acid identity of 67-77% to fad2 of Glycine, Arabidopsis and Brassica species [8].
• The identification of SREBP-1c as a key regulator of D6D suggests that the major physiological function of SREBP-1c in liver may be the regulation of phospholipid synthesis rather than triglyceride synthesis [13].
• In meat eaters or omnivores which can acquire arachidonic acid from food, the main consequences of D6D loss will be deficiencies of GLA, dihomogamma-linolenic acid (DGLA) and prostaglandin (PG) E1 [12].

Other interactions of FADS2

• This work identifies Delta-6 desaturase/FADS2 as the major fatty acid desaturase in human sebaceous glands and suggests that the environment of the sebaceous gland permits catalysis of the sebaceous-type reaction and restricts catalysis of the polyunsaturated fatty acid type reaction [5].

References