Delta-5 and Delta-6 Desaturases: Crucial Enzymes in Polyunsaturated Fatty Acid-Related Pathways with Pleiotropic Influences in Health and Disease

  • Federica Tosi
  • Filippo Sartori
  • Patrizia Guarini
  • Oliviero Olivieri
  • Nicola Martinelli
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 824)

Abstract

Polyunsaturated fatty acids (PUFA) play pleiotropic and crucial roles in biological systems. Both blood and tissue levels of PUFA are influenced not only by diet, but to a large extent also by genetic heritability. Delta-5 (D5D) and delta-6 desaturases (D6D), encoded respectively by FADS1 and FADS2 genes, are the rate-limiting enzymes for PUFA conversion and are recognized as main determinants of PUFA levels. Alterations of D5D/D6D activity have been associated with several diseases, from metabolic derangements to neuropsychiatric illnesses, from type 2 diabetes to cardiovascular disease, from inflammation to tumorigenesis. Similar results have been found by investigations on FADS1/FADS2 genotypes. Recent genome-wide association studies showed that FADS1/FADS2 genetic locus, beyond being the main determinant of PUFA, was strongly associated with plasma lipids and glucose metabolism. Other analyses suggested potential link between FADS1/FADS2 polymorphisms and cognitive development, immunological illnesses, and cardiovascular disease. Lessons from both animal models and rare disorders in humans further emphasized the key role of desaturases in health and disease. Remarkably, some of the above mentioned associations appear to be influenced by the environmental context/PUFA dietary intake, in particular the relative prevalence of ω-3 and ω-6 PUFA. In this narrative review we provide a summary of the evidences linking FADS1/FADS2 gene variants and D5D/D6D activities with various traits of human physiopathology. Moreover, we focus also on the potentially useful therapeutic application of D5D/D6D activity modulation, as suggested by anti-inflammatory and tumor-suppressing effects of D6D inhibition in mice models.

Keywords

Cancer Cardiovascular disease Delta-5 desaturase Delta-6 desaturase FADS FADS2 Inflammation Polyunsaturated fatty acids 

7.1 Introduction: From the Pleiotropic Effects of PUFA to the Increasing Interest on Desaturases

Polyunsaturated fatty acids (PUFA) have heterogeneous and crucial functions in the human body (Fig. 7.1). First of all, they are fundamental structural components of cell membranes, in particular at level of central nervous system, and their incorporation into the phospholipid layer may alter membrane’s fluidity and selective permeability (e.g. an increase of PUFA incorporation enhances membrane’s fluidity, while saturated fatty acids make the membrane more rigid). By this way they can influence the function and activity of membrane-associated receptors and enzymes [1, 2, 3, 4]. As paradigmatic example, the increase of membrane’s fluidity has been associated with improved insulin sensitivity due to both augmented number and higher affinity of insulin receptors on cellular surface [5]. PUFA are also well recognized to be a major fuel source for energy metabolism and are beta-oxidized within mitochondria by most of cells in the body [6].
Fig. 7.1

The heterogeneous functions and pleiotropic effects of polyunsaturated fatty acids (PUFA)

PUFA can influence cellular function by regulating several metabolic pathways, acting as both direct and second messengers. Long-chain PUFA may act directly as ligands for transcription factors like sterol regulatory element binding protein 1 (SREBP-1), nuclear factor κB (NF-κB), hepatocyte nuclear factor 4α (HNF-4α), and peroxisome proliferator-activated receptors (PPARs), which are involved in lipogenesis, steroid hormones synthesis, and FA oxidation [7]. For instance, ω-3 PUFA are known to influence several nuclear receptors modulating lipid metabolism (e.g. PPARs, HNF-4α, liver X receptor (LXR), and farnesol X receptor (FXR)) with hypotriglyceridemic effects [8]. As second messengers, PUFA regulate the synthesis of several inflammatory mediators, like eicosanoids that represent the key link between PUFA and inflammation. Eicosanoids are lipid mediators of inflammation and include a variety of compounds (prostaglandins, thromboxanes, leukotrienes, lipoxins, isoprostanes, hydroxyl and epoxy fatty acid). In particular arachidonic acid (AA, 20:4 ω-6) is the most important substrate for the synthesis of the strongest pro-inflammatory eicosanoids [9]. AA-derived metabolites have been demonstrated to play crucial roles in chronic inflammation, as well as in cardiovascular disease (CVD) and cancer [10, 11, 12, 13]. Noteworthy, AA is also the substrate for the synthesis of anandamide and other endocannabinoids, which are neuromodulatory mediators with a very broad range of biological effects involved in several pathophysiological conditions, from neurodegenerative to inflammatory disorders, metabolic derangements, CVD, cancer, and cachexia [14, 15, 16]. A recent study showed that the activation of Nlrp3 inflammasome by endocannabinoids promotes beta cell failure in type 2 diabetes [17].

From a chemical point view, fatty acids are carboxylic acids with a long aliphatic chains, which may be either saturated or unsaturated. Long-chain fatty acids having 16–20 carbon units are the most abundant cellular fatty acids, while very long-chain fatty acids having more than 20 carbon units are much less abundant. PUFA are chemically characterized by the presence of two or more double bonds in their hydrocarbon chain. They are classified according to (i) the number of carbon atoms, (ii) the number of double bonds and (iii) the position of the double bond nearest to the terminal methyl group. Four families of PUFA have been identified on the basis of these structural characteristic, that are ω-3, ω-6, ω-7, and ω-9 PUFA. However, ω-3 and ω-6 PUFA are universally recognized as the most important series [3, 4]. From this point of view it should be emphasized that both ω-3 and ω-6 long-chain PUFA are particularly important in humans in order to maintain the function of brain and central nervous system [18, 19]. On the other hand, ω-3 and ω-6 PUFA appear to differ profoundly for some of their biological and clinical consequences. It is worth noting that ω-6 PUFA-derived eicosanoids (e.g. prostaglandin E2, thromboxane A2, leukotriene B4) have strong proinflammatory effects, while those derived from ω-3 PUFA (e.g. prostaglandin E3, thromboxane A3, leukotriene B5) may have anti-inflammatory action (Fig. 7.2) [20, 21]. The different properties of ω-3 and ω-6 PUFA are particularly evident in cardiovascular field, where ω-3 PUFA – in particular the long chain eicosapentenoic (EPA, 20:5 ω-3) and docosahexaenoic acid (DHA, 22:6 ω-3) – are usually considered as good friends for cardiovascular health. The favorable effects of ω-3 PUFA are complex and pleiotropic, including preventing cardiac arrhythmias, lowering plasma triglycerides, decreasing blood pressure, and reducing platelet aggregability [22, 23]. The pioneering GISSI-Prevention trial showed that 1 g daily consumption of ω-3 PUFA reduced cardiovascular mortality after myocardial infarction, mainly by preventing sudden death [24]. Already in 2002, the American Heart Association (AHA) recommended ω-3 PUFA for patients with ischemic heart disease and subjects with hypertriglyceridemia [25]. In 2004, the United States Food and Drug Administration (FDA) also approved ω-3 PUFA for hypertriglyceridemia therapy [23, 26]. In contrast, ω-6 PUFA with their proinflammatory effects appear as a potentially dangerous bad company for heart and vessel. Consistently, high levels of AA in adipose tissue have been associated with an increased risk of myocardial infarction [27, 28].
Fig. 7.2

Eicosanoids derived from ω-3 or ω-6 polyunsaturated fatty acids present different proinflammatory activities

The PUFA profile in human body reflects both dietary intake and endogenous metabolism. The precursors of both ω-3 and ω-6 PUFA (α-linolenic (ALA, 18:3 ω-3) and linoleic acid (LA, 18:2 ω-6), respectively) are essential fatty acids and therefore cannot be synthesized in mammals. Dietary sources for ALA are canola, flaxseed and rapeseed oils, walnuts and leafy green vegetables, while LA is contained in eggs, poultry, cereals, margarine, sunflower and corn oils [29]. In the most of Western diets, ALA and in particular LA contribute more than 95 % of dietary PUFA intake, that in turn represents up to 20 % of dietary fat [30]. Long chain-PUFA are then synthesized endogenously from ALA and LA by reactions of both insertion of additional double bonds, catalyzed by desaturases, and elongation of the acyl chain, catalyzed by elongases (Fig. 7.3). The conversion of LA and ALA into longer PUFA involves only a relatively small proportion of the essential fatty acids introduced with the diet, since the majority undergoes beta-oxidation reactions to accomplish the needs of energy metabolism [31]. Noteworthy, both ω-3 and ω-6 PUFA compete for the same set of enzymes in this pathway, although a preferential affinity for ω-3 rather than ω-6 PUFA has been demonstrated [3].
Fig. 7.3

The ω-3 and ω-6 fatty acid metabolism pathways

Elongation involves the addition of two carbon units to aliphatic chain and this process takes place mainly in the endoplasmic reticulum catalyzed by membrane-bound enzymes [32]. Seven isozymes of elongation of very long chain fatty acid proteins (ELOVL 1–7) have been identified so far, each characterized by specific substrate specificity and function [32, 33]. ELOVL1-3-6-7 show a selective preference for saturated and monounsaturated fatty acids, whereas ELOVL2-4-5 have that for PUFA. ELOVL1-5-6 genes are ubiquitously expressed, while ELOVL2-3-4-7 genes are characterized by specific tissue expression (although the physiological role of such differentiated distribution remains still unknown) [34].

Desaturases are microsomal enzymes. They are thought to be a component of a three-enzyme system which includes also cytochrome b5 and NADH-cytochrome b5 reductase [35, 36]. The delta-5 (D5D) and delta-6 desaturases (D6D) are key enzymes in both ω-3 and ω-6 PUFA metabolism, allowing the formation of long chain metabolites from dietary ALA and LA. Noteworthy, the D6D-mediated conversion of either ALA to stearidonic acid (SA, 18:4 ω-3) or LA to γ-linolenic acid (GLA, 18:3 ω-6) is the rate limiting step of both ω-3 and ω-6 PUFA metabolic pathways.

D5D and D6D are encoded by FADS1 and FADS2 genes, respectively. The FADS gene cluster is located on chromosome 11 (11q12-13.1) and includes a third gene, i.e. FADS3, that shares 52–62 % sequence identity with FADS1/FADS2 genes and encodes for a yet unidentified protein [37]. Both blood and tissue levels of PUFA are influenced to a large extent by genetic heritability. Up to 28 % of variation of blood levels AA is due to genetic variation, while such value is about 10 % for AA precursors [38]. Preliminary studies in the German and Italian populations showed very strong associations between FADS1-FADS2 polymorphisms and PUFA levels in both serum phospholipids and red blood cell membranes [38, 39]. Minor alleles of single nucleotide polymorphisms (SNPs) in FADS1/FADS2 genes were usually associated with higher LA and lower AA levels, suggesting a corresponding impairment of desaturases activity. Subsequent analyses replicated such associations in several different populations of European, Asian, and African descent [40, 41, 42, 43, 44, 45]. Consistently with these results, genome-wide association studies (GWAS) confirmed FADS locus as the strongest genetic predictor of plasma phospholipid PUFA [46]. If the relationship between FADS genetic variants and PUFA levels is unquestionable, it should be noted that the mechanisms by which FADS polymorphisms may influence desaturase activity and PUFA concentration remain largely unknown. Only few functional studies have been performed on this topic so far. A recent study showed an influence of polymorphism rs968567 on FADS2 promoter activity by luciferase reporter gene assays [47]. On the other hand, in another study the polymorphism rs3834458 did not appear to directly affect FADS2 promoter activity [48].

PUFA status has been related with several outcomes in human health, from neuronal development to psychiatric illnesses [49, 50], from inflammatory to immunologic response [51], from metabolic disorders to CVD [13, 23]. Both FADS polymorphisms and desaturase activities have been accordingly associated with the same diseases during the last decades [13, 52]. Hence, the interest on FADS genes and desaturases exponentially increased, as testified by the progressively higher number of publications on these issues (Fig. 7.4). In this narrative review we try to summarize the main evidences linking FADS genes, D5D, and D6D with human diseases, addressing also the potential therapeutic applications.
Fig. 7.4

Publications on delta-5/delta-6 desaturase (a) and FADS1/FADS2 (b) over 15 years

7.2 Delta-5 and Delta-6 Desaturase Activities in Human Diseases

Desaturase activity is assessed in vitro or in animal studies by measuring the rate of the conversion of radiolabeled fatty acids to their respective products [53], but ethical and practical reasons preclude this possibility in humans. On the other hand, FADS gene expression could be determined in liver cells, but this approach would require obtaining liver biopsies. Therefore, the direct measurement of desaturase activity is not feasible for the use in large scale epidemiological studies [54]. Nonetheless, the use of product to precursor ratio as a surrogate measure to estimate desaturase activity is well established. Indirect information can be acquired by the analysis of lipid composition of either human plasma or cell membranes (usually from the easily collectable red blood cells) [13, 53]. The product to precursor ratios are commonly performed on ω-6 fatty acids (owing to the ω-3 final products, like EPA and DHA, may be more strongly influenced by dietary intake) and can estimate the global desaturase activity (with AA/LA ratio), as well as the specific D5D (with AA/DGLA ratio) or D6D activity (with GLA/LA). The product to precursor ratio approach has been used in many clinical studies linking desaturase activities and diseases in humans (Fig. 7.5) [13].
Fig. 7.5

Associations of delta-5 (D5D)/delta-6 desaturase (D6D) activity with clinical phenotypes and human diseases. D5D and D6D activities were generally estimated by fatty acid product to precursor ratio. “Whole desaturase activity” refers to arachidonic to linoleic acid ratio, thus including the metabolic passages of both D5D and D6D

Several studies have associated desaturase activity with dysmetabolic phenotypes and cardiovascular risk factors. An increased whole desaturase activity was found in patients with essential hypertension [55], as well as in subjects with insulin resistance, obesity, and metabolic syndrome [56, 57].

The relationship with type 2 diabetes is particularly impressive. Several studies have investigated the potential link between desaturase activity and alteration in glucose metabolism (for a review, see reference n. [54]). Most of these studies showed independent and significant correlations of estimated desaturase activities with diabetes risk, inverse for D5D and direct for D6D.

High D6D activity and low D5D activity were shown to be associated with insulin resistance [58] and, most importantly, to predict the development of diabetes [59, 60, 61, 62]. Moreover, an increased D6D and a decreased D5D activity have been found in Japanese children with abdominal obesity [63] and both could predict the long-term development of the metabolic syndrome, which is a cluster of metabolic abnormalities with a physiopathological core represented by insulin resistance [64]. All these results prompt to hypothesize that desaturase activity plays a role in the pathogenesis of diabetes and may influence the individual susceptibility to diabetes.

Non-alcoholic steatohepatitis (NASH) is a disease characterized by inflammation and fat accumulation in the liver. It is usually associated with metabolic derangements, like obesity, plasma lipids abnormalities, insulin resistance, and type 2 diabetes. NASH is increasingly recognized as a common liver condition, may progress to cirrhosis, and potentially would become the leading cause of liver transplantation worldwide [65]. Increased D6D and decreased D5D estimated activities have been found in patients with non-alcoholic fatty liver disease as compared with normal subjects [66]. Consistently, mice with high-fat diet-induced obesity and NASH showed an increased expression of D5D and D6D at both mRNA and protein level in the cells of the liver. Noteworthy, a combined D5D/D6D inhibitor, CP-24879, significantly reduced intracellular lipid accumulation and inflammatory injury in hepatocytes [67]. Moreover, CP-24879 exhibited superior antisteatotic and anti-inflammatory actions in hepatocytes from fat-1 mice, that express an ω-3 desaturase allowing the endogenous conversion of ω-6 into ω-3 fatty acids and restoring hepatic ω-3 content [68].

A relationship between desaturases activities and CVD has been also proposed. In a community-based prospective population of 50-year old men D6D activity showed a direct association with cardiovascular mortality (HR 1.12 with 95% CI 1.00–1.24), while D5D had an inverse correlation (HR 0.88 with 95% CI 0.80–0.98) [69]. Accordingly, high D6D activity was associated with most of cardiovascular and metabolic risk factors, while triglycerides and fasting insulin were beneficially related to D5D activity [70]. In a previous work of our group within the angiographically-controlled Verona Heart Study, using the AA/LA ratio as a surrogate measure of “overall” desaturase activity, we found that this ratio was higher in patients with coronary artery disease (CAD). The proportion of CAD increased progressively from the lowest to the highest AA/LA tertile and after adjustment by multiple logistic regression AA/LA remained associated with CAD independently from all the traditional cardiovascular risk factors (the highest versus the lowest tertile OR 2.55 with 95 % CI 1.61–4.05). Moreover, the serum concentration of C-reactive protein measured by high sensitivity methods (hs-CRP) also increased progressively across AA/LA tertile [71]. Thus, it appeared reasonable to hypothesize that inappropriately high desaturase activity may indicate a peculiar susceptibility to the inflammatory stimuli involving the arterial wall during the atherosclerotic process. Actually, an increased desaturase activity – especially in an ω-6 rich environment, like that generated by the current Western diet – may lead to a greater AA bioavailability, thus favoring the synthesis of AA-derived mediators and vascular inflammatory damage involved in the pathogenesis of atherosclerosis [13, 71]. There is a great interest in the role of AA-derived eicosanoids in atherosclerosis [9]. The leukotriene pathway has been associated with CVD in both mice and humans [9, 72, 73]. Consistently with such point of view, accumulation of AA in adipose tissue has been associated with a greater risk of myocardial infarction (MI), suggesting a proatherosclerotic/prothrombotic role of AA excess [27, 28], although the results were sometimes object of controversy [74]. Remarkably, a recent study in Chinese Han population confirmed that AA/LA ratio level was higher in CAD patients [75].

Our result suggesting that high “overall” desaturase activity may be harmful for cardiovascular health [71] is consistent with those about D6D activity [69, 70]. Taking into account that D6D is the rate-limiting step of the whole PUFA pathway, this concordance appears as biologically plausible. On the other hand, D5D is the key enzyme in synthesizing long-chain PUFA and increased D5D activity has been associated with high plasma levels of EPA and DHA [76]. Accordingly, D5D activity has been inversely associated with triglycerides, fasting insulin [70], cardiovascular mortality [69], and incident risk of ischemic heart disease [76].

Inflammation and AA-derived mediators play crucial roles also in cancer biology. Increased AA metabolism and the related eicosanoid formation are characteristic in various types of cancer cells [77, 78]. AA-derived pro-inflammatory and pro-angiogenic eicosanoids, which are produced by tumor cells and their surrounding stromal cells, are key mediators in their crosstalk and can accelerate tumor growth and metastasis development through several mechanisms [10]. Selective inhibition of D6D with SC-26196 (a highly selective inhibitor of D6D) has been shown to inhibit tumorigenesis in two mice models of intestinal cancer. Noteworthy, this effect on tumorigenesis was abrogated by concomitant treatment with dietary AA, suggesting that such influence was due to the interference with AA-related pathways [79]. More recently, the group of Kang showed that D6D activity was up-regulated during melanoma and lung tumor growth in mice and AA/LA ratio was positively correlated with tumor size. Most importantly, the suppression of D6D activity, either by knocking down D6D expression with RNAi or by inhibiting D6D enzyme activity with SC-26196, reduced tumor growth. Accordingly, the content of AA and AA-derived eicosanoids was significantly decreased in tumor tissues. Both D6D-RNAi and SC-26196 did not show any significant tumor growth suppression in vitro, suggesting that blocking D6D is not directly toxic for cancer cells. The authors rather proposed that the anti-tumor effect of D6D inhibition could be due to its impact on the tumor microenvironment, modulating inflammation and angiogenesis [80].

The composition of phospholipid fatty acids of separated mononuclear blood cells was altered and an increased D6D activity has been found in patients with acute lymphoblastic leukemia, but not in acute myeloid leukemia [81]. Moreover, in vitro studies showed that the inhibition of D6D could reduce the growth of different leukemia cell types [82]. A study evaluating PUFA composition of subcellular fractions from healthy and cancerous kidney tissues, revealed lower LA content and D5D activity, and higher AA, ALA, EPA contents and D6D activity in renal cell carcinoma than in healthy renal tissue [83]. An increased D6D activity was found in human breast cancer tissue [84]. On the other hand, a previous case–control study evaluating fatty acid composition of erythrocyte membrane could not clearly support that desaturase activity influence the development of breast cancer [58].

Long-chain PUFA are fundamental constituents of human central nervous system. The availability of both ω-3 and ω-6 PUFA influences brain development and growth, particularly during the perinatal period and in early life. Alterations in PUFA composition have been associated with different neurological and neuropsychiatric illnesses [85, 86]. Therefore, also desaturase activities have been hypothesized to influence neurological and psychiatric functions in health and disease. Post-mortem studies on prefrontal cortex of patients with schizophrenia showed a greater D6D activity index. Moreover, FADS2 mRNA expression was higher in patients with schizophrenia than in controls and such difference was independent of antipsychotic medications [87, 88]. FADS2 mRNA expression was significantly elevated also in the prefrontal cortex of patients with bipolar disorder [89]. On the other hand, D6D and D5D activities were not different between patients with recurrent major depressive disorders and age- and sex-matched healthy controls [90].

Finally, a reduction of D5D activity has been estimated from analysis of whole blood fatty acids in patients with cystic fibrosis, especially in the case of severe disease [91]. In contrast, further studies showed that cystic fibrosis cells in culture had an increased expression of D5D and D6D enzymes [92, 93].

7.3 FADS1/FADS2 Gene Variants in Human Diseases: From the Earlier Reports to Genome-Wide Association Studies (GWAS)

FADS1 and FADS2 genes encode D5D and D6D, respectively. They are located on chromosome 11 (11q12-13.1), in reverse orientation, and separated by <11 kb region. Cloning of both D5D and D6D was performed in 1999 [35, 36]. A third gene, named FADS3, is included in this cluster, but no functional role has been yet attributed to the FADS3 putative transcriptional product [94]. A recent study showed that FADS3 does exist under multiple protein isoforms depending on the mammalian tissues [95]. Since all the three FADS genes share a common location and had a similar structure, it has been hypothesized that they arose evolutionary from gene duplication, acquiring substrate specificity during the evolution [37, 52].

Earlier studies on FADS1-FADS2 polymorphisms disclosed a very strong associations with PUFA levels in both serum phospholipids and red blood cell membranes [38, 39]. As previously mentioned, minor alleles of single nucleotide polymorphisms (SNPs) in FADS1/FADS2 genes were usually associated with higher precursor and lower product levels, suggesting an impairment of desaturases activity. Remarkably, GWAS confirmed FADS locus as the strongest genetic predictor of plasma phospholipid PUFA [46, 96].

Taking into account the pleiotropic effects of PUFA, it appears biologically plausible that FADS gene variants associated with different desaturase activity can have an impact on several pathological conditions. Therefore, although the mechanisms by which FADS polymorphisms influence desaturase activity and PUFA concentration remain largely unknown, studies analyzing the possible relationship between FADS genotype and human diseases flourished (Fig. 7.6).
Fig. 7.6

Associations of FADS genotypes with clinical phenotypes and human diseases. Those relations which have been confirmed by genome-wide studies are accordingly indicated (GWAS)

The pioneering study of Schaeffer et al. suggested that FADS genotypes associated with low desaturase activity (and thus low AA bioavailability) may have a lower risk of immunological disease, like allergic eczema and atopic rhinitis [38]. Noteworthy, about 20 years ago the results of genome-wide search for linkage to traits associated with allergic asthma identified one linkage on chromosome 11q13, i.e. where FADS gene cluster is located [97]. More recent studies suggested that the association between dietary intake of PUFA and allergic diseases, as well as the association between breastfeeding and asthma, might be modulated by FADS gene variants in children [98, 99]. Furthermore, a recent study found that FADS polymorphisms may influence hs-CRP plasma concentration in young adults [100].

According to the concept of the potentially harmful effects of an excess of AA-derived pro-inflammatory mediators, we showed within the Verona Heart Study population that FADS polygenic models (including rs174545, rs174570, rs17583, and rs1000778 SNPs) and FADS haplotypes associated with high AA/LA ratio had increased hs-CRP plasma concentration and were more represented in CAD patients than in CAD-free subjects [71]. Noteworthy, we emphasized the deleterious effects of FADS genotypes associated with high desaturase activity could be particularly evident in an ω-6 rich diet, like it was that of Verona Heart Study. Previously, another study investigated the possible relationship between FADS genes and CVD. In the Costa Rican population a common deletion variant in the FADS2 promoter (rs3834458) was associated with a decrease in serum AA and EPA, as well as triglyceride, but not with MI. Interestingly, the authors of this work suggested that the results may have been masked by the high availability of the ω-3 ALA in the diet of Costa Rican population [101]. It should be noted that GWAS did not found so far any significant association between FADS gene locus and CAD/MI [102], speculatively because of the diet variability in the different populations included.

In contrast, GWAS approach identified FADS locus as an important genetic determinant of plasma concentration of all plasma lipids, from triglyceride to HDL- and LDL-cholesterol [103, 104, 105], even in populations with different ethnic background [106]. FADS1 variant associated with high transcription level were linked with both high production of long chain ω-3 PUFA and favorable effects on plasma lipids, like lowering triglyceride and increasing HDL-cholesterol plasma concentration [103]. Noteworthy, a very recent study examining 188,577 individuals using genome-wide and custom genotyping arrays identified FADS locus as one of the four (the others were CETP, TRIB1, and APOA1) which were associated with all lipid traits, i.e. total, HDL-, and LDL-cholesterol, and triglyceride [107]. Overall, these data suggest a direct genetic influence on lipid parameters, but not so strong to affect secondarily also the clinical (cardiovascular) outcomes.

A relationship between FADS gene locus and glucose metabolism has been also disclosed. In a GWAS involving more than 120,000 subjects FADS1 rs174550 polymorphism was associated with fasting glucose and had a weak relation with diabetes risk [108]. In another study FADS1 rs174550 was associated with abnormalities in early insulin secretion [109]. In the EPIC-Potsdam Study FADS1 rs174546, which is in complete linkage with the above mentioned rs174550, was associated with both D5D and D6D activities (with minor allele carriers having both lower D5D and D6D activities) [40]. As previously cited in the paragraph on D5D and D6D activities in human diseases, most of studies investigating the association between desaturase activity and diabetes disclosed opposite trends of correlation for either D5D or D6D activity. More precisely, there was an inverse correlation of D5D and a direct correlation of D6D with diabetes risk [59, 60, 61, 62]. Analysis of FADS polymorphisms by adjusting for the estimated D5D and D6D activities confirmed contrasting influences on diabetes risk [62]. Consequently, it was suggested that a reciprocal counterbalance (e.g. FADS genotypes associated with both high D5D and high D6D activity, or vice versa) might result in an overall weak association of FADS genotypes with diabetes [54, 62]. This concept may provide a possible explanation for some controversial results about the relationship between FADS gene locus and glucose metabolism traits [109, 110, 111, 112, 113, 114].

The key role of desaturases in human metabolism has been further emphasized by a comprehensive analysis of phenotypes using a GWAS with non-targeted metabolomics. In such analysis FADS gene locus presented one of the strongest association with metabolic traits (P = 8.5×10−116 for FADS1 rs174547 association with 1-arachidonoyl-glycerophosphoethanolamine/1-linoleoyl-glycerophosphoethanolamine ratio) [115].

Long-chain PUFA, like AA and DHA, are crucial to enhance cognitive development. Breastfeeding exposes babies to increased concentration of AA and DHA and has been found to improve significantly the cognitive development with higher later intelligence quotient (IQ) [116]. Remarkably, the association between breastfeeding and IQ was moderated by FADS2 rs174575 polymorphism in two birth cohorts. More precisely, there was no effect of breastfeeding on IQ in GG homozygotes, while breastfed children carrying the C allele had a striking IQ advantage over those who were no breastfed [116]. In contrast with these data, in a subsequent study rs174575 GG homozygotes exhibited the greatest difference between feeding methods with no breastfed GG children performing worse than other no breastfed children [117]. It is worthy to note that FADS1 and FADS2 genetic variants have been shown to influence the PUFA composition of breast milk in pregnancy and lactation [118]. Subsequent studies indicated that FADS1/FADS2 gene locus controls brain expression of FADS1 and that its genetic variance in combination with breastfeeding and/or food intake might alter PUFA composition in the brain, thereby potentially influencing cognition [119]. Another recent study confirmed the favorable role of maternal AA and DHA on fetal neural development and suggested that the endogenous synthesis of long-chain PUFA regulated by FADS genes, in particular FADS2, may also be important [120]. Therefore, although some results are controversial and no definitive proof has been provided, FADS1/FADS2 and D5D/D6D may have a role in the complex and still shadowy field of cognitive development.

7.4 Lessons from Animal Models

Mice models have provided precious information about the biological role of desaturases and their various effects in different pathological conditions (Fig. 7.7, top panel). Stoffel and colleagues investigated a model of genetically defined FADS2-deficient (fads2−/−) mice [121]. FADS2 deficiency was confirmed to prevent the processing of LA and ALA to long-chain ω3- and ω6-PUFA. Consistently, eicosanoids synthesis was abolished and macrophages failed to synthesize leukotrienes in immune response. Surprisingly, the viability of fads2−/− mice was unimpaired. Key parameters of carbohydrate and lipid metabolism remained unchanged in spite of the lack of long-chain PUFA. Male and female mice were sterile with disrupted spermiogenesis and folliculogenesis, respectively. Platelet aggregation and thrombus formation were inhibited. Thus, bleeding time was increased, while fads2−/− mice were protected from vessel thrombosis inducted by vascular injury [121].
Fig. 7.7

Lessons on desaturases from animal models and rare clinical disorders in humans

Fan and colleagues investigated a model of FADS1 knockout mice [122]. As expected, the levels of DGLA and AA were reciprocally altered in all the tissues. The lack of AA-derived eicosanoids was associated with perturbed intestinal crypt proliferation, immune cell homeostasis, and an amplified sensitivity to acute inflammatory challenge. Mice failed to thrive and died before 12 weeks of age. Noteworthy, dietary supplementation with AA extended the longevity of FADS1 knockout mice to levels comparable to wild-type mice [122].

Pharmacological interventions on mice furnished intriguing data. Studies in mice treated with CP-24879, a mixed D5D/D6D inhibitor, suggested that desaturase inhibition may have anti-inflammatory properties by decreasing the levels of AA and, consequently, of AA-derived eicosanoids [123]. The specific D6D inhibitor SC-26196 had marked anti-inflammatory properties and decreased edema to the same extent as indomethacin did in mice [123]. All these results supported the hypothesis of a significant role of desaturases in inflammation and suggested desaturases as a target for the development of new anti-inflammatory drugs. Moreover, the mixed inhibitor CP-24879 was shown to reduce lipid accumulation and inflammatory injury in hepatocytes of mice with NASH induced by high-fat diet [67].

Finally, the selective inhibition of D6D with SC-26196 has been shown to block tumorigenesis and/or reduce tumor growth in different mice models of neoplasia, such intestinal cancer, lung cancer, and melanoma (see also the previous paragraph “Delta-5 and delta-6 desaturase activities in human diseases”) [79, 80]. Thus, D6D inhibition could be a potential target as well for the therapy and the prevention of cancer.

7.5 Lessons from Rare Clinical Disorders in Humans

The thorough observation of rare, genetic and metabolic disorders has often represented a useful source of clinical and scientific information in the history of medicine. Very low levels of D6D activity have been described in patients with the Sjögren-Larsson syndrome, a genetic disease which is caused by mutations in ALDH3A2 gene codifying for fatty aldehyde dehydrogenase and is characterized by ichthyosis, spastic diplegia, and mental retardation [124, 125]. About 10 years ago, a nucleotide insertion in the transcriptional regulatory region of the human FADS2 gene (i.e. an insertion of thymidine between positions −942 and −941 upstream of the translation start site) was described [126]. This mutation caused a sixfold decrease in promoter activity and thus D6D deficiency with severe impairment of LA to AA conversion. The subject carrying this mutation was clinically characterized by feeding intolerance, growth failure, corneal ulcerations, marked photophobia, and skin abnormalities. Noteworthy, all these clinical signs and symptoms significantly improved after diet supplementation with a mixture of LA and DHA [126]. D5D deficiency has been suggested in two brothers with multineuronal degeneration, mental retardation, neurosensory hearing loss, retinitis pigmentosa, progressive muscular atrophy, hepatosplenomegaly, and adrenal failure (Fig. 7.7, bottom panel) [127].

7.6 A “Desaturase Hypothesis” for Atherosclerosis

The influence of desaturases on biological systems is extremely complex and pleiotropic, so that every oversimplification about clinical consequences of such activities (e.g. high desaturase activity is dangerous, while low desaturase activity is advantageous, or vice versa) looks as inadequate. Most importantly, the biological effects of desaturase activity could be modulated by the different balance between ω-3 and ω-6 PUFA. The case of CVD may represent a paradigmatic example from this point of view. A high desaturase activity in a ω-3 PUFA-rich environment would increase the cardioprotective EPA and DHA. On the other hand, a high desaturase activity in a ω-6 PUFA-rich environment would increase the AA bioavailability, potentially favoring the synthesis of proinflammatory eicosanoids and the consequent inflammatory vascular damage. In the Verona Heart Study population, within a clinical context characterized by a larger prevalence of ω-6 PUFA, a higher desaturase activity estimated by means of AA/LA ratio was associated with both hs-CRP concentration and increased risk of CAD. Moreover, FADS haplotypes associated with higher AA/LA ratio had also higher hs-CRP concentration and were more represented within the CAD population [71].

Desaturases appear therefore as Janus-faced enzymes with both favorable and unfavorable effects according the relative balance/imbalance of PUFA [13]. In the current Western diet the ω-6/ω-3 PUFA ratio is estimated to be about 15/1, instead of 1/1 as in prehistoric or tribal human populations. Noteworthy, a balance between ω-6 and ω-3 PUFA is thought to have existed for millions of years during the evolution of mankind [128] and only recently the imbalance to ω-6 PUFA may have unraveled the proinflammatory and potentially harmful consequences of high desaturase activity [13]. Finally, the variants in FADS genes suggest that individuals with different genotype may require different amount of dietary PUFA to achieve comparable biological effects [129]. Accordingly with this hypothesis, subjects with FADS genotype predisposing to high desaturase activity may be more susceptible to the proinflammatory effects of diets rich in ω-6 PUFA and deficient in ω-3 PUFA (Fig. 7.8), but at the same time may have particular benefits from approaches reducing the ω-6/ω-3 PUFA ratio imbalance, like ω-3 PUFA supplementation [13].
Fig. 7.8

A “desaturase hypothesis” for atherosclerosis. Desaturases could be considered as Janus-faced enzymes with both favorable and harmful effects for cardiovascular health. In subjects following a Western diet rich in ω-6 PUFA, a high desaturase activity would predispose to more pronounced vascular inflammatory damage. Accordingly, subjects with FADS genotype predisposing to high desaturase activity may be more susceptible to the proinflammatory effects of diets rich in ω-6 PUFA and deficient in ω-3 PUFA. AA arachidonic acid, ALA α-linolenic, DHA docosahexaenoic acid, EPA eicosapentaenoic acid, LA linoleic acid

7.7 An Evolutionary Hypothesis for Desaturases

The synthesis of long-chain PUFA is particularly important in humans. Actually, humans are extremely dependent on long-chain PUFA because of their large brain, which requires high amounts of long-chain PUFA, like DHA and AA, in order to maintain its function [18, 19]. A recent and fascinating study of Gyllensten’s group performed genome-wide genotyping and targeted resequencing of FADS region in different human populations, as well as analyzed genomic data from archaic hominids and other primates [130]. Present-day humans were shown to have mainly two common haplotypes associated with different desaturase activity: the haplotype D (frequency 62.1 %) associated with a higher ability to generate long-chain PUFA and the haplotype A (frequency 33.0 %). Noteworthy, the results suggested that the haplotype D appeared after the split from Neanderthals – around 500,000 years ago – but prior to the exodus of modern humans from Africa – 50,000–100,000 years ago. Moreover, this haplotype showed evidence of positive selection, possibly by providing advantage in environments with limited availability of dietary long-chain PUFA. The authors hypothesized that the advantage of having a faster biosynthesis of long-chain PUFA might have turned into a disadvantage with the modern Western diet, like in a sort of evolutionistic Yin-Yang. Actually, haplotype D might have been beneficial when food sources of long-chain PUFA were scarce. On the other hand, within an environmental context characterized by high ω-6 PUFA intake the haplotype D might favor the synthesis of AA-derived eicosanoids leading to inflammatory damage and its harmful clinical consequences, including CVD (Fig. 7.9) [130]. This idea seems to fit perfectly with the above mentioned “desaturase hypothesis” for atherosclerosis [13] according to an evolutionistic and holistic point of view.
Fig. 7.9

An evolutionary hypothesis for desaturases. Humans are extremely dependent on long-chain PUFA because of their large brain, which requires high amounts of long-chain PUFA. FADS haplotype associated with a higher ability to generate long-chain PUFA (haplotype D) might have been beneficial when food sources of long-chain PUFA were scarce. On the other hand, within an environmental context characterized by high ω-6 PUFA intake the haplotype D may favor the synthesis of eicosanoids leading to inflammatory damage and its harmful clinical consequences. Therefore, the advantage of having a faster biosynthesis of long-chain PUFA might have turned into a disadvantage with the modern Western diet, like in a sort of evolutionistic Yin-Yang

In summary, the more efficient ability to generate long-chain PUFA could have been selected as a favorable trait during the evolution of mankind. Only during the last century (the genetic selection pressure needs much more time than one century to be effective), the dramatic and rapid changes in environmental context and dietary intake have unraveled the potentially harmful effects of high desaturase activity. More precisely, the skill to generate long-chain PUFA (and the related FADS genotypes) may change into detrimental if ω-6 PUFA are largely prevalent, favoring eicosanoids-mediated inflammatory damage [11, 13].

7.8 Concluding Remarks

PUFA metabolism is crucial in humans. D5D and D6D are well recognized as main predictors of PUFA variability, thereby influencing several biological mechanisms [13, 30, 52]. Both alterations of D5D/D6D activities and FADS1/FADS2 polymorphisms have been associated with a lot of different diseases. However, the complex and heterogeneous effects of desaturase activity, as well as the multifaceted interactions with PUFA dietary intake, have made it difficult so far to moving this group of enzymes from the bench to the bedside.

Nonetheless, the modulation of D5D/D6D activity appears as a potentially promising target in different pathological conditions, as testified by both anti-inflammatory and tumor-suppressing effects of D6D inhibition in mice models [79, 80, 123]. On the other hand, the deleterious consequences which have been observed in case of severe lack of desaturase activity in both animal models [121, 122] and humans [124, 125, 126, 127], advise against an indiscriminate inhibition of desaturases. Rather they address the need for search of tissue-specific modulators of D5D/D6D activity. To this aim, we require a better comprehension of the processes, like the epigenetic ones, differently regulating FADS1/FADS2 expression. Moreover, the specificity of either D5D or D6D activity should be taken into account (e.g. D6D and D5D activities have been differently associated with different diseases), as well as the environmental context in which the enzymes are working (e.g. ω-6-rich diets may enhance the pro-inflammatory effect of high desaturase activity). Further studies addressing all these issues are strongly warranted and may contribute to the development of both tailored dietary strategies for reducing the risk of illness and specific modulations of D5D/D6D activity for treating diseases associated with alterations in PUFA homeostasis.

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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Federica Tosi
    • 1
  • Filippo Sartori
    • 1
  • Patrizia Guarini
    • 1
  • Oliviero Olivieri
    • 1
  • Nicola Martinelli
    • 1
  1. 1.Department of MedicineUniversity of VeronaVeronaItaly

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