Omega-3 and omega-6 polyunsaturated fatty acids: Dietary sources, metabolism, and significance — A review

Life Sciences 203 (2018) 255–267

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Review article

Omega-3 and omega-6 polyunsaturated fatty acids: Dietary sources, metabolism, and significance — A review

T

⁎

Ramesh Kumar Saini , Young-Soo Keum Department of Crop Science, Konkuk University, Seoul 143-701, Republic of Korea

A R T I C LE I N FO

A B S T R A C T

Keywords: Docosahexaenoic acid (DHA) Eicosapentaenoic acid (EPA) Eicosanoids Fish oil

Linoleic acid (LA) (n−6) and α-linolenic acid (ALA) (n−3) are essential fatty acids (EFAs) as they cannot be synthesized by humans or other higher animals. In the human body, these fatty acids (FAs) give rise to arachidonic acid (ARA, n−6), eicosapentaenoic acid (EPA, n−3), and docosahexaenoic acid (DHA, n−3) that play key roles in regulating body homeostasis. Locally acting bioactive signaling lipids called eicosanoids derived from these FAs also regulate diverse homeostatic processes. In general, ARA gives rise to pro-inflammatory eicosanoids whereas EPA and DHA give rise to anti-inflammatory eicosanoids. Thus, a proportionally higher consumption of n−3 PUFAs can protect us against inflammatory diseases, cancer, cardiovascular diseases, and other chronic diseases. The present review summarizes major sources, intake, and global consumption of n−3 and n−6 PUFAs. Their metabolism to biosynthesize long-chain PUFAs and eicosanoids and their roles in brain metabolism, cardiovascular disease, obesity, cancer, and bone health are also discussed.

1. Introduction Naturally occurring fatty acids (FAs) can be classified into three categories based on the number of double bonds present in side chains: saturated FAs (SFAs, no double bonds), monounsaturated FAs (MUFAs, a single double bond), and polyunsaturated FAs (PUFAs, ≥2 double bonds). FAs can be further classified by their carbon chain length and the position of the first double bond on methyl terminal (omega; ω; or n−FAs) (Fig. 1). Thus, all-cis-9,12,15-octadecatrienoic (α-linolenic acid, ALA, C18:3) and all-cis-9,12-octadecadienoic (linoleic acid, LA, C18:2) are n−3 and n−6 FA, respectively. These FAs are essential FAs (EFAs) as they cannot be produced within the human body. Long-chain (LC) FAs contain > 12 carbon atoms. FAs containing 22 or more carbon atoms are referred as very-long-chain (VLC) FAs [1]. In the body, LCPUFAs (LA and ALA) are converted to very long chain VLC-PUFAs by fatty acyl-CoA synthetases, Δ6- and Δ5-desaturases, and their respective elongases designated as elongation of very long FAs (ELOVL). All-cis5,8,11,14,17-eicosapentaenoic (EPA, 20:5, n−3), all-cis-7,10,13,16,19docosapentaenoic (DPA, C22:5, n−3), all-cis-4,7,10,13,16,19-docosahexaenoic (DHA; C22:6, n−3), and all-cis-5,8,11,14-eicosatetraenoic (arachidonic acid, ARA, C20:4, n−6) are major LC- and VLC-PUFAs that play important roles in animal body [1]. PUFAs are generally considered to have beneficial health effects. However, n−3 and n−6 PUFAs have opposing effects on metabolic functions in the body. Diets enriched in n−6 PUFAs are associated with

⁎

Corresponding author. E-mail address: [email protected] (R.K. Saini).

https://doi.org/10.1016/j.lfs.2018.04.049 Received 30 January 2018; Received in revised form 19 April 2018; Accepted 25 April 2018 Available online 30 April 2018 0024-3205/ © 2018 Elsevier Inc. All rights reserved.

inflammation, constriction of blood vessels, and platelet aggregation [2]. Acute inflammatory responses can protect host against infection and injury [3]. However, uncontrolled and inappropriately activated acute inflammation due to excess of inflammatory stimuli provides an ideal tumor microenvironment. Persistent inflammation has been linked to cancer risk and metastasis [4,5]. Similarly, chronic inflammation induces atherosclerosis which can lead to acute cardiovascular disease (CVD). In contrast, n−3 PUFAs help resolve inflammation and alter the function of vascular and carcinogen biomarkers, thus reducing the risk of cancer and CVD [6,7]. In addition to CVD and cancer, n−3 PUFAs provide substantial protection against other chronic and metabolic diseases such as diabetes, obesity, osteoporosis, neurological degeneration, and bone fractures [1,4,8,9]. Considering these opposing effects of n−3 and n−6 PUFAs, absolute contents and proportion of these PUFAs, especially dietary LA and ALA, play a significant role in regulating body homeostasis of inflammation and anti-inflammation, vasodilatation and vasoconstriction, bronchoconstriction and bronchodilation, and platelet aggregation and antiaggregation [9]. These PUFAs may exert these effects by themselves to regulate diverse sets of homeostatic processes or by locally acting bioactive signaling lipids called eicosanoids derived from ARA, EPA, and DHA [2]. Considering these potential benefits, an adequate and balanced intake of n−3 PUFAs is potentially beneficial for protection against chronic and metabolic diseases. In the present review, we have outlined the primary source and global consumption of n−3 and n−6

Life Sciences 203 (2018) 255–267

R.K. Saini, Y.-S. Keum

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PUFAs. Their metabolism to biosynthesize LC-PUFAs and lipid mediators (eicosanoids) and their roles in brain metabolism, CVD, obesity, cancer, and bone health are also discussed in this treatise.

Table 1 Contents of n−3 and n−6 fatty acid in selected plant and animal-based foods. Source: USDA National Nutrient Database for Standard Reference, Release 28 (2015), http://ndb.nal.usda.gov/ndb/search, accessed on 29th September 2017.

2. Sources of n−3 and n−6 PUFAs

Food

Most crop seeds and vegetable oils, including canola, soybean, corn, and sunflower oils, are major sources of n−6 FAs in the form of LA with low proportions of n−3 FAs (ALA). Contrasting to n−6 FAs, the intake of n−3 FAs is usually inadequate because of their limited sources [10]. Exceptionally, seeds of chia (Salvia hispanica), perilla (Perilla frutescens), and flax (Linum usitatissimum) are abundant in ALA (Table 1). Green leafy vegetables also contain high proportions (60–70% of total FAs) of PUFAs in the form of ALA [11–13]. Diet based on fish, fish oil, beef, and lamb can also supply EPA, DPA, DHA, and ARA that can be directly utilized for normal physiological functions in the body (Table 1). Wild (marine) fishes contain more n−3 PUFAs than cultivated (farmed) fishes since most marine fishes feed on phytoplankton and zooplankton that are abundant in n−3 PUFAs whereas farmed fishes consume feed made of cereal and vegetable oils that contain more proportions of n−6 FAs. Similarly, cold-water fishes accumulate higher proportions of LC n−3 PUFAs that help them to adapt to cold environment than warmwater fishes. In plant and animal-based food, majority (≈98%) of LC-PUFAs are found in the form of triacylglycerols (TAGs), followed by phospholipids (PLs; e.g., lecithin) and diacylglycerols (DAGs), cholesterol esters (CE), and fat-soluble vitamin esters (e.g., retinyl palmitate and tocopherol acetate). They have shown significantly different levels of bioavailability in animals [14]. PLs are more bioavailable due to their amphiphilic nature with superior water-dispersibility and greater susceptibility to phospholipases compared to glycerolysis of TAGs [14]. Moreover, LC-PUFAs supplements in the form of PLs are more efficient than TAGs due to higher uptake of PLs by the brain. For instance, Krill oil contains nearly 35% of DHA in the form of PLs. Thus, it is considered more efficient than fish oil as LC-PUFAs in fish oil are found in the form of TAGs [15]. Structures of DHA bound PLs and TAGs are shown in Fig. 2. The absorption of DHA can be further increased if it is present in

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8.56 18.23 10.66 10.97 4.21 3.80

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0.01 5.84 27.36 33.76 23.83

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sn-1 position of dietary PLs or in lysophosphatidylcholine (LPC or lysolecithins) since it would escape hydrolysis by pancreatic phospholipase A2 (PLA2) which releases FAs from the sn-2 position of glycerol. It would be absorbed as lysophosphatidylcholine (LPC) and then converted to PC by acyltransferase before entering the lymph. The presence 256

Life Sciences 203 (2018) 255–267

R.K. Saini, Y.-S. Keum

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In animals, primarily in the endoplasmic reticulum of liver cells, biosynthesis of LC-PUFAs starts with Δ6-desaturation by adding a double bond at the 6th CeC bond position from the eCOOH end of LA and ALA, thus generating γ-linolenic acid (GLA, C18:3, n−6) and stearidonic acid (SDA, C18:4, n−3), respectively (Fig. 3). Delta-6 desaturase is a rate-limiting enzyme in mammals and humans. In continuation by two-carbon elongation, these Δ6-desaturated FAs are elongated to yield dihomo-γ-linolenic acid (DGLA, C20:3, n−6) and eicosatetraenoic acid (ETA, C20:4, n−3), respectively, by Δ6 specific elongase. Finally, a Δ5-desaturase adds a double bond at the 5th CeC bond and carries out one more desaturation to produce ARA (C20:4, n−6) and EPA (C20:5, n−3), respectively. By Δ17-desaturase, GLA, DHGLA, and ARA can be converted to SDA, ETA, and EPA, respectively. In mammals (called the Sprecher pathway), EPA undergoes two successive elongation cycles. First, docosapentaenoic acid (DPA, clupanodonic acid; C22:5, n−3) is generated. Then tetracosanolpentaenoic acid (C24:5, n−3) is produced which then yields tetracosahexaenoic acid (THA; C24:6, n−3) by Δ6-desaturation. This C24 PUFA is then subjected to β-oxidation by which its chain is shortened by two carbons to yield VLC-PUFA docosahexaenoic acid (DHA; C22:6, n−3), the final product [21] (Fig. 1). Since members of n−6 and n−3 FUFAs compete for corresponding desaturase and elongase enzymes, bioconversion of LA and ALA to their respective LC and VLC-FUFAs in humans depends on the ratio of ingested n−6 and n−3 FAs. In human hepatoma cells, the highest rate of formation of EPA and DHA occurs when a 1:1 ratio of LA and ALA is present [22]. After incubation of cells with a mixture of 1:1 of LA: ALA, conversion rates are 16% for EPA and 0.7% for DHA. In a review, Brenna et al. [23] have summarized that increasing the intake ALA with decreasing LA intake is most effective way to improve n−3 LC-PUFA status. Compared to ALA and EPA, DHA supplementation is most effective way to improve body DHA levels. Biosynthesized LC- and VLC-PUFAs such as ARA, EPA, and DHA are stored in esterified form in phospholipids or neutral glycerides after esterification with hydroxyl groups of the glycerol backbone of phospholipids or glycerides. When required, these FAs can be mobilized/rehydrolyzed by phospholipase A2 to form eicosanoids and other autacoids. ARA and EPA are parent compounds for eicosanoid production. ARA can be converted to series 2 prostaglandins (A2, E2, I2, and thromboxane A2) by cyclooxygenases-2 (COX-2). However, series 4 leukotrienes (B4, C4, and E4) are biosynthesized from ARA with the action of lipoxygenases (5-LOX). Similarly, cytochrome P450 (CYP) epoxygenase and epoxide hydrolase dependent metabolism of ARA can lead to the synthesis of epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) [24]. In contrast to ARA, EPA is metabolized to series 3 prostaglandins (B3, D3, E3, I3, and thromboxane A3) and Series 5 leukotrienes (B5, C5, and D6) with the help of COX-2 and 5-LOX, respectively. DHA can also be metabolized to autacoids such as D-series resolvins (Resolvin D1 to Resolvin D6), protectins (Neuroprotectin D1), and maresins (MaR1 and MaR2). Biosynthesis of major eicosanoid with its parental substrate of n−6 PUFAs (ARA) and n−3 PUFAs (EPA and DHA) is summarized in Fig. 4.

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Fig. 2. Structures of EPA/DHA bound triacylglycerols (TAGs) and phospholipids. Fish oil/Krill oil containing EPA/DHA are mainly linked to β (sn-2) position of TAG (a) whereas Seal oil EPA/DHA are primarily bound to α (sn-1) position of TAG (b). Krill oil DHA is found in the form of phospholipid (phosphatidylcholine-DHA) attached at sn-2 position (c). LysophosphatidylcholineDHA represents a preferred physiological carrier of DHA to the brain (d).

of DHA in plasma PC increases its subsequent uptake by the brain [15]. Binding position of EPA and DHA to TAGs also affects their absorption, cholesterol metabolism, and eicosanoid productions [16]. Previous studies [17,18] have demonstrated that EPA/DHA bound to the sn-1 position (α position) of TAGs (e.g., seal oil) provide superior effects on lipid metabolism than those bound to the sn-2 position (β position) (e.g., squid oil). Binding positions of DHA to PLs or TAGs have shown significant differential effects on absorption and its subsequent uptake in the brain. However, only a few studies are available in this context. Thus, more comprehensive studies are needed to establish the relationship between the binding position of EPA/DHA to PLs/TAGs which can influence lipid absorption and transportation. 3. Metabolism of n−3 or n−6 PUFAs and production of eicosanoids It has been established that dietary LA and ALA play crucial roles in maintaining tissue n−3 and n−6 LC-PUFAs levels [19]. These LCPUFAs are significantly accumulated and produced in specific tissues based on their selective need. LA and ALA are also critically responsible for producing various classes of pro-inflammatory and anti-inflammatory eicosanoids. Eicosanoids are bioactive signaling lipids derived from ARA, dihomo-gamma-linolenic acid (DGLA), EPA, and DHA by cyclooxygenase (COX-1 and COX-2), lipoxygenase (5-LOX and 15LOX), and epoxygenases (cytochrome P450 or CYP). LA and ALA have competing roles in the synthesis of eicosanoids. High intake of ALA favors the production of anti-inflammatory eicosanoids since n−3 FAs are preferred substrates for desaturase and elongase enzymes involved in eicosanoid biosynthesis. Almost all higher plants, algae, some fungi, and lower animals (e.g., Caenorhabditis elegans) possess Δ12-desaturases to convert oleic acid (C18:1, cis-9) into LA and Δ15-desaturases to convert LA to ALA [20]. However, animals including humans are deficient in these desaturases necessary to convert oleic acid to LA and ALA. Thus, LA and ALA are considered essential FAs in human diet.

4. Dietary intake of PUFAs Owing to competing roles of n−6 and n−3 PUFAs in the production of anti-inflammatory and inflammatory eicosanoids, balanced intake of n−6 and n−3 FAs is necessary to evade chronic diseases and to maintain good health. The recommended dietary ratio of n−6/n−3 FAs for health benefits is 1:1–2:1. However, in typical Western diets, the ratio of n−6/n−3 is 15/1 to 16.7/1 [25]. In the last few decades, the n−6/n−3 ratio in human breast milk has also increased due to changes in maternal dietary fat which is the vital determinant in the increasing prevalence of childhood overweight and obesity [26]. The emergence of agribusiness along with processed foods, grain fed livestock and fishes, and hydrogenation and refining of vegetable oils with increased use of soybean oil in food preparations have reduced the 257

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R.K. Saini, Y.-S. Keum

n-6 Fatty acid

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α-Linolenic acid (ALA, C18:3, n-3) Rate Limiting step (Inhibited by LA)

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Eicosatetraenoic acid (C20:4, n-3)

Dihomo-g-linolenic acid (DGLA, C20:3, n-6)

Inflammation, vasoconstriction, and platelet aggregation

Δ 5-desaturase Arachidonic acid (ARA, C20:4, n-6)

Δ 5-desaturase Eicosapentaenoic acid (EPA, C20:5, n-3) ELOVL 5 and 2

ELOVL 5 and 2

Lipoxygenase (LOX) (Series 4): Leukotrienes B4, C4, E4

Δ6-desaturase

Stearidonic acid (C18:4, n-3)

γ-Linolenic acid (C18:3, n-6)

Cyclooxygenase (COX) (Series 2): Prostaglandins A2, E2, I2 Thromboxane A2

n-3 Fatty acid

Docosatetraenoic acid (Adrenic, C22:4, n-6)

Anti-inflammation, vasodilatation and anti-aggregation Lipoxygenase (LOX) (Series 5): Leukotrienes B5, C5, D6

Docosapentaenoic acid (DPA, C22:5, n-3) ELOVL 2

ELOVL 2 Tetracosatetraenoic acid (C24:4, n-6)

Cyclooxygenase (COX) (Series 3): Prostaglandins B3, D3, E3, I3 Thromboxane A3

Tetracosapentanoic acid (C24:5, n-3)

Δ6-desaturase

Mitochondrion

Δ6-desaturase

Tetracosapentaenoic acid (C24:5, n-6)

tetracosahexanoic acid (C24:6, n-3) β-oxidation

β-oxidation

Docosahexaenoic acid (DHA; C22:6, n-3)

Peroxisome

Docosapentaenoic acid (Osbond acid, C22:5, n-6) Resolvins and Protectins

Fig. 3. Biosynthetic pathway of very long chain (VLC) n−3 and n−6 polyunsaturated fatty acids (PUFAs) from their common precursors.

index (≤4% EPA + DHA) was observed in Central and South America (Guatemala and Brazil), Europe (Greece, Ireland, Italy, Serbia, Turkey, and UK), North America (Canada and USA), the Middle East (Iran and Bahrain), Southeast Asia (India), and Africa (Kenya). Data on global intakes of n−3 fat studied by Micha et al. [28] shared several similarities with the map of blood levels presented by Stark et al. [29]. Both studies observed low n−3 index in most of the world, which provides a strong indication of global risk for chronic diseases. In a systematic review, Sioen et al. [30] have reported suboptimal intakes of n−3 and n−6 PUFA among population in 17 European countries. Across all population groups, including infants, children, adolescents, the elderly, and pregnant/ lactating women, mean LA intake was below the recommended intake (RI) in 48% of these countries, with low intake more likely in lactating women (25% counties), adolescents (56% counties), and the elderly (> 65 years; 34% counties). Also, mean ALA intake was below the RI of European Food Safety Authority (EFSA) in 23% countries, with the lowest intake found among the elderly in 50% countries. Across all population groups, mean EPA and DHA intakes were lower than the EFSA recommendation in 74% of countries, with the lowest intake found in pregnant and lactating women (RI of EPA + DHA: 250 mg/day), infants (RI: 100 mg DHA/ day), and adolescents (RI: 250 mg DHA/day). Based on ample evidence from epidemiologic and controlled clinical studies, Gebauer et al. [31] have made recommendations of dietary n−3 FAs, including ALA, EPA, and DHA to prevent deficiency symptoms. They have recommended flaxseed and flaxseed oil, walnuts and walnut oil, and canola oil as ALA sources. Consumption of ≈500 mg/day of EPA and DHA from two fish meals per week is recommended for cardiovascular disease risk

content of n−3 FAs and increased n−6 FAs in the diet. In the United States, changes in consumption of n−3 and n−6 FAs during the 20th century have been estimated by per capita consumption of current foods (1999-C) and foods produced by traditional early 20th century practices (1909-T). Results have shown that per capita consumption of soybean oil has increased 1000-fold from 1909 to 1999. The availability of LA and ALA has increased from 2.79% to 7.21% and 0.39% to 0.72%, respectively. Similarly, the ratio of LA to ALA has been increased from 6.4 in 1909-T to 10.0 in 1999-C. The increase in the intake of LA has caused declines in tissue n−3 fatty acid status (36.81% in 1909-T to 22.95% in 1999-C) and n−3 index (ratio of erythrocyte EPA + DHA to total FAs) [27]. Micha et al. [28] have assessed patterns of global consumption of key dietary fats and oils by country, age, and sex in 1990 and 2010. Their results have revealed that global saturated fat, dietary cholesterol, and trans-fat intakes are stable whereas n−6, seafood n−3, and plant n−3 fat intakes are increased between 1990 and 2010. In 2010, global mean intake of seafood n−3 fats was 163 mg/ day, with significant regional variation (50 to 700 mg/day) and national variation (5 to 3886 mg/day). Highest intakes were observed in Iceland (1189 mg/day), Barbados (1178 mg/day), Japan (995 mg/day), Maldives, the Seychelles, Denmark, Malaysia, South Korea, and Thailand. Stark et al. [29] have also conducted a global survey of reports published on n−3 fatty acid status and found the highest omega-3 index (> 8% EPA + DHA in erythrocytes) is found in countries with the highest seafood intake, including Sea of Japan region (Japan and South Korea), Scandinavia (Denmark, Greenland and Norway), and areas with indigenous populations or populations not fully adapted industrial based (Western pattern) diets. In contrast, very low status of omega-3 258

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R.K. Saini, Y.-S. Keum

Extracellular EPA

Extracellular ARA

ARA 5-LOX

Thromboxane (TXA2, TXB2)

Prostaglandins (PGA2, PGE2, PGF2α, PGI2)

Phospholipase A2

Phospholipase A2

Phospholipase A2

COX-2

Phospholipid

Phospholipid

Phospholipid

COX-1

Extracellular DHA

DHA

EPA 12/15-LOX Maresin (MaR1)

CYP

15-LOX

Lipoxins (LXA4) Leukotrienes (LTE4, LTB4, LTC4)

Epoxyeicosatrienoic acids (5,6-EET, 8,9-EET, 11,12EET, 14,15-EET)

5-LOX

COX-2

Prostaglandins (PGI3, PGI3α, PGB3, PGD3, PGE3)

15-LOX D Series Resolvins (RvD1, RvD2, RvD3, RvD4, RvD5, RvD6)

Thromboxane (TXA3)

Leukotrienes (LTB5, LTC5)

E Series Resolvins (RvE1, RvE2)

Membrane Receptors

Signaling molecules Vasoconstriction ↔ Vasodilation

DNA

mRNA

Bronchoconstriction ↔ Bronchodilation Inflammation ↔ Resolution of inflammation

Fig. 4. Production of eicosanoids from arachidonic acid (AA; n−6 FUFAs), eicosapentaenoic acid (EPA; n−3 FUFAs), and docosahexaenoic acid (DHA; n−3 PUFAs) with their mode of action.

reduction. To treat existing CVD, ≈1000 mg/day of EPA and DHA from fish oil supplements is recommended. The cardioprotective effect of n−3 FAs has been reviewed and it is suggested that n−6 FAs, total energy, and fats should be individually considered for the general public to comply with dietary recommendations for PUFAs [32]. In general, a standard dose of 1 g/day EPA and DHA is recommended by cardiac societies. More preciously, it has been proposed that omega-3 index (% of EPA + DHA to total FAs) of RBC should be > 8% to minimize sudden cardiac death as it is associated with 90% less risk for sudden cardiac death compared to n−3 index of < 4% [33]. A low status of LC n−3 PUFA in middle-aged German women (40–60 years) has been documented [34] with an average omega-3 index of 5.5. Low intake of oily fish has been attributed to be the primary cause of the low status of n−3 index in the blood of the studied population. Lower EPA level, lower ratio of EPA/ALA, but higher ratio of DHA/EPA has been recorded in women taking hormonal contraceptives than women without hormonal contraception. This might be due to estrogen effect which is known to affect the conversion efficiency of ALA [35]. EFSA has suggested that there is no necessity to add ARA or EPA to infant formula (IF) or follow-up formula (FOF) [36]. However, some studies have reported that ARA and EPA are essential in addition to DHA. The essentiality of ARA (in addition to DHA) for brain growth and function has been established using Δ6-desaturase knockout mice and a novel artificial rearing method [37]. Mice deficient in Δ6-

desaturase cannot produce ARA, EPA, or DHA from dietary LA or ALA. Thus, they can be used as a suitable animal model to evaluate the essentiality of these key PUFAs. It has been demonstrated that supplementation with only ARA or only DHA is insufficient for optimal brain or central nervous system (CNS) development. ARA was found to be indispensable for normal body growth during the lactation period [37]. These authors have concluded that only a combination of ARA and DHA can reverse the dysfunction caused by Δ6-desaturase deficiency. Owing to the absolute requirement of DHA for brain development, its sufficient intake in the body should be achieved. Fish, fish oil, and beef contain a substantial amount of EPA and DHA. Their consumption can meet such requirement. However, plant-based diet is completely deficient in EPA and DHA with varying amounts of ALA [10]. For vegetarians, ALA is the only precursor for DHA. In the body, DHA can synthesize from ALA. However, this process is strongly rate-limited in humans, with conversion rate as low as 0.25–7.0% for EPA and 0.01–0.05% for DHA, leading to relatively less production of EPA and DHA in the body [38]. The conversion of ALA to EPA and DHA depends on several dietary and genetic factors, including ratio of LA and ALA in the diet, deficiency of other nutrients, gender difference, and polymorphisms in desaturases and elongases [25,35,39]. Since LA and ALA compete for the same elongase and desaturase during the biosynthesis of LC-PUFAs, low ratio of LA to ALA favors the biosynthesis of n−3 LC-PUFAs [25]. It has been observed that vitamin A (retinol, retinal, retinoic acid) deficiency can 259

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reduce DHA in liver and colon tissue membranes probably by decreasing the activation of retinoid X receptor (RXR) since 9-cis retinoic acid is the potent ligand of RXR [39]. The conversion efficiency to generate DHA from ALA is better in young women compared to that in men due to estrogen effect [35]. In addition to gender differences and amount and ratio of n−6 to n−3 FAs in diets, single nucleotide polymorphisms in fatty acid desaturase 1 (FADS1), FADS2, FADS3, and fatty acid elongase (ELOVL2) also affect the bioconversion of EPA and DHA. A unique FADS haplotype (haplotype D; positive selection in African populations) with more efficient biosynthesis of essential LC-PUFAs from precursors has been identified in humans compared to hominid ancestors [40]. This haplotype D is likely to be advantageous to humans living in environments with limited access to these FAs. Considering the differential ability to biosynthesize LC-PUFAs with specific human SNPs, FADS genotyping can also be included as a diagnostic tool for dietary recommendations. In clinical studies, these factors should be considered for accurate interpretation of results. Fish is the major source of n−3 LC-PUFAs. It has been extensively used in the food industry to obtain n−3 PUFA concentrates [41]. Dietary supplements of n−3 LC-PUFAs are widely available. They are commonly in the form of TAGs, free fatty acid (FFA), ethyl esters (EEs), and PLs. Both FFA and EE forms are derived from natural sources of fish oil TAG. More recently, krill oils obtained from Antarctic krill (Euphausia superba) (a small swimming crustacean) containing a significant portion of n−3 LC-PUFA in PLs form are also increasingly found in the Australian market [42]. Due to higher absorption and bioavailability of phospholipids compared to TAGs of fish oil, a lower dose (62.8% compared to fish oil) of EPA + DHA from krill oil is sufficient to meet desired plasma levels of EPA and DHA without observing any adverse effects [43]. Direct supplementation of foods with essential FAs is also an attractive strategy to deliver recommended levels of PUFAs [44]. However, several challenges such as consumer acceptability, delivering desired levels with a balanced ratio of n−3 and n−6 FAs, bio-efficacy, bioavailability, and cost-effectiveness require further exploration.

improve contents of n−3 FAs in seed oil. They have certain advantages over conventional sources of PUFAs. For example, pollution of marine ecosystems has resulted in high accumulation of toxic dioxins, polychlorinated biphenyls (PCBs), heavy metals, and organochlorine pesticides in fish [50]. Additionally, low contents of n−3 PUFAs in farmed fishes and wild fish stock are insufficient in order to satisfy recommended EPA and DHA intake levels [51]. Thus, genetically modified crops can serve as future sources of n−3 PUFAs. In the last decade, many genes encoding n−3 PUFA biosynthetic pathways have been identified, characterized, and used for biofortification of n−3 PUFAs in annual oilseed crops and animals. Transgenic Camelina sativa expressing Δ6-desaturase, Δ6 fatty acid elongase gene, Δ5-desaturase, Δ12-desaturase, and n−3-desaturase gene have been found to accumulate over 20% of EPA which could effectively substitute for fish oil in aquafeeds to improve their nutritional quality for human diet [52]. Similarly, soybean plants engineered with Δ6-desaturase can produce significant high amount of stearidonic acid (SDA) (≈20% v/v) which could be used as viable plant-based alternatives to provide significant intakes of EPA to archive desired n−3 index in human [53]. Strategies to improve the intake of n−3 FAs in the diet discussed above have their advantages and disadvantages [45]. For instance, n−3 FAs enriched eggs produced by feeding laying hens with fish meal or canola/ linseed oil are commercially viable as a good source of LC n−3 FUFAs [47]. However, concerns over cholesterol present in yolk cannot be ignored. Higher susceptibility of PUFAs to oxidation, insolubility in water, undesirable rancid odor and taste are also barriers in the development of fortified food products. However, these problems can be eliminated by oil microencapsulation which can significantly delay or inhibit oxidation and mask the undesirable fishy odor and flavor [54,55]. Feeding grain and vegetable oil based diet is the major cause of low contents of n−3 FAs in farmed fishes. Contents of EPA and DHA in farmed fishes can be increased by feeding them algal biomass [51]. However, this strategy is not well studied yet. Further studies are needed to determine its effectiveness and commercial viability.

5. Approaches to enhance LC-PUFAs in food

6. Role of PUFA in infection, inflammation, cancer, and CVD

The low intake of n−3 PUFAs in most parts of the world increases the risk for chronic diseases. Up to date, several strategies have been proposed to increase the intake of n−3 PUFAs in the body, including the following: (i) Increased consumption of fatty fish and other n−3 PUFAs-rich foods, (ii) Fortification of food products with fish oil, krill oil, or ALA, (iii) Enhancement of n−3 PUFAs in animal products by feeding n−3 PUFAs-rich diets, and (iv) Fortification of n−3 PUFAs in oilseed crops by genetic engineering [45,46]. It has been demonstrated that feeding animals with ALA-rich diet can increase contents of n−3 LC-PUFA in animal-derived products. However, the magnitude of increase in n−3 LC-PUFA contents appears to be dependent on the type of diet supplementation [10]. 2 to 5-fold higher EPA and DHA has been recorded in breast and thigh meat of broilers fed with high ALA-rich flaxseed oil for 6 weeks [47]. Nutritional quality of milk is improved through organic production by shifting fatty acid composition [48]. The organic milk has been found to contain 25% less n−6 FAs but 62% more n−3 FAs than conventional milk, yielding a significantly lower n−6/n−3 ratio in organic milk (2.28) compared to conventional milk (5.77). Milk from cows consuming significant amounts of grass and legume-based forages contains higher contents of ALA, EPA, and DPA compared to cows fed substantial quantities of grains, especially corn. Different aspects of dietary enrichment of eggs with n−3 fatty have been reviewed [49]. These authors have concluded that feed supplementation with LC n−3 PUFAs in the form of fish oil or heterotrophic microalgae (e.g., Nannochloropsis sp.) is more beneficial compared to supplementation with their precursor ALA through flaxseed due to the relatively low conversion of ALA to EPA and DHA by humans as well as by laying hens. Metabolically engineered oilseed crops are also beneficial to

Cancer, CVD, diabetes, obesity, osteoporosis, and bone fractures are major chronic diseases related to diet and physical activity patterns. Among dietary sources, lipids play critical roles in the prevention and occurrence of all these diseases. Relative amounts n−3 and n−6 FAs consumed are believed to be very critical [4]. Protective effects of n−3 PUFAs are mediated by alterations in properties of cancer cells by decreasing their proliferation, invasion, and metastasis while increasing their apoptosis. In addition, they affect host cells by regulating inflammation, immune response, and angiogenesis [4]. DHA plays a key role in maintaining membrane fluidity of retina and the brain which is essential for proper neurological and cognitive functions [56]. Moreover, ARA, EPA, and DHA are converted into eicosanoids that can regulate diverse sets of homeostatic and inflammatory processes linked to numerous diseases, including infection, inflammation, cancer, and CVD [2]. Since n−6 LC-PUFAs derived eicosanoids are pro-inflammatory whereas n−3 LC-PUFAs derived eicosanoids have anti-inflammatory activities, the amount of n−6 and n−3 FAs in a person's diet largely affects the production of pro-inflammatory and anti-inflammatory eicosanoids. Biological activities of ARA, EPA, and DHA derived eicosanoid are summarized in Table 2. As illustrated in Fig. 5, n−3 FUFAs have multiple roles, including the following: (i) Resolving inflammation and prevention of infection, (ii) cancer prevention, (iii) brain development, and (iv) obesity, diabetes, and CVD prevention. 6.1. PUFAs in brain metabolism DHA is the most abundant n−3 LC-PUFA in mammalian CNS, membrane lipids of brain's grey matter (≈5 g in the human brain, 15–20% total FAs), and visual elements of the retina [8]. The presence 260

PGI2 PGF2α PGE2

ARA/COX-1

261

PMN, monocytes, and macrophages E. coli peritonitis

Human dermal fibroblasts Skeletal muscle

Macrophages

RvD2 RvD3

RvD4 PDX

PD1

BCC cells, macrophages

[96] [97] [98] [89] [99] [100] [93] [101,102] [103,104] [105,106]

Asthma CKD, cancer SLE, cystic fibrosis, and IMPA CAD CAD

↑Vascular permeability, constrict bronchial smooth muscle, bronchoconstriction ↑Neutrophil recruitment, ↑local cell death signals, kidney inflammation, ↑murine melanoma growth Anti-inflammatory, resolution of inflammation, Phagocytosis of PMN Vasodilation, vascular protective ↓Platelet aggregation, vasoconstriction, ↓cardiac ischemic injury, ↓arteriosclerosis, ↑angiogenesis. ↓Neutrophil transmigration through the endothelial cell ↓Adenoma number and size, ↓synthesis of PGE2 Apoptosis of leukemia stem cells ↓Murine Melanoma growth ↓PMNs infiltration, ↓IL-12 p40, TNF-α, IL-23 and IL-6 production, ↑Lipoxin A4, interferon-γ ↓PMNs infiltration ↓TNF-α, IL-6, and IL-8 production, ↓pro-inflammatory response of BEC cells to organic dust, ↓PMN infiltration in murine peritonitis, stimulating human macrophages efferocytosis, ↑tissue regeneration, ↓pain ↑Human T cell apoptosis, ↓obesity-induced insulin resistance, ↑macrophage clearance in MI

↑Phagocytosis of apoptotic PMNs

↓PMN infiltration, ↑phagocyte clearance of bacteria, and accelerate resolution ↑Leukocyte phagocytosis of E. coli, ↓neutrophils pro-inflammatory cytokines, chemokines, MMP-2 and MMP-9 ↓Neutrophilic infiltration, ↑uptake of apoptotic PMN ↑IL-6 from skeletal muscle

[93–95]

CVD

Staphylococcus aureus infections Treatment of insulin resistance and type 2 diabetes Resolution of inflamed tissues

Type 2 diabetes and obesity, myocardial infarction (MI) Bacterial infections Bacterial infections

Leukemia Cancer IBD, including Crohn's disease, allergy Inflammatory disorders ↓Inflammatory effects of environmental dust exposures, tissue regeneration

Anaphylaxis, type 2 inflammation in the lung

Cystic fibrosis, HCC

↑Bicarbonate secretion, ↑hepatocellular carcinoma (HCC) Stimulate nociceptive neurons Mast-cell maturation, accumulation of ILC2s, development of type 2 inflammation in the lung, ↑ neutrophil migration across endothelial cells stimulated with TNF-α Development of atherosclerotic lesions, ↑platelet aggregation, vasoconstriction

[113]

[111] [112]

[109] [110]

[107,108]

[92]

[91]

[86,87] [88] [89,90]

[83] [84] [85]

IAPH Atherosclerosis

↓Pulmonary arterial hypertension, ↓platelet aggregation Vasoconstriction Triggers mast cell activation, ↑vascular permeability and edema formation

Reference

Disease target

Action

BECs: bronchial epithelial cells; CKD: chronic kidney disease; COX: cyclooxygenase; CRC: colorectal cancer; CVD: cardiovascular disease; CYP: cytochrome P450; HCC: hepatocellular carcinoma; IBD: inflammatory bowel disease; ILC2s: Group 2 innate lymphoid cells; IMPA: immune-mediated polyarthritis; IPAH: idiopathic pulmonary arterial hypertension; LOX: lipoxygenase; MI: myocardial infarction; PASMCs: pulmonary artery smooth muscle cells; PMNs: polymorphonuclear leukocytes; SLE: systemic lupus erythematosus; TRPA: transient receptor potential.

DHA/15-LOX

DHA/12 or 15LOX

Murine peritonitis Brachial arteries Vascular endothelial cell membrane Endothelial cell Human CRC cells Murine models of leukemia Murine melanoma Mouse peritonitis, lungs

Adipose tissue

LAX4 LXB4 EETs PGI3 PGD3 PGE3 Δ12-PGJ3 LTB5 RvE1 RvE2 MaR1

ARA/15-LOX ARA/CYP EPA/COX-2

Neutrophil, murine melanoma

Platelets, endothelial cells, macrophages, and monocytes Endothelium

Mast-cell, lung

PASMCs Vascular smooth muscle cells Mouse peritoneal and bone marrowderived mast cells Colonic epithelial cells, HCC cells

Organs or cell target

RvD1

LTC4, LTE4, LTD4 LTB4

ARA/5-LOX

EPA/5-LOX

TXA2

ARA/COX-2

15-keto-PGE2 PGJ2 PGD2

Mediator

Parent PUFA/

Table 2 Biological activities of ARA, EPA, and DHA derived eicosanoids.

R.K. Saini, Y.-S. Keum

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R.K. Saini, Y.-S. Keum

II. Cancer prevention

I. Resolving inflammation and prevention of infection • • • •

↓COX-2 and 5-LOX (↓Pro-inflammatory cytokines IL-1, IL-2, IL-

•

↓COX-2 and PGE2 (↓Tumor cell growth and invasion)

6, IL-8, IL-1β, TNFa, TNF-2, and MCP1)

•

↑Tumor suppressor protein BRCA1

↓Adhesion molecules (ICAM--1, VCAM-1, ELAM-1), mediated by

•

↓Cancer associated weight loss (cachexia)

PPARα and PPARγ (↓Rheumatoid arthritis)

•

↓Protein kinases (JNK, MAPK, p38, NF-Κb)

↓TLR and NOD signaling (↓IBD)

•

↑PPARα and PPARγ mediated apoptosis

↑SPM (resolvins, protectins, and maresins), ↓PMN chemotaxis,

•

Regulate Ca+2 channels to activate eIF2α kinase (↓Oncogenes and

↓Ca+2

G1 cyclins)

mobilization (↑ tissue regeneration)

•

↓Pro-inflammatory response of BECs to organic dust

•

↑Macrophages efferocytosis

•

↑Non-enzymatic lipid peroxidation to induce apoptosis in tumor cells

n-3 PUFAs IV. Obesity, diabetes, and CVD prevention

III. Brain development •

↑Mental and motor skill development

•

↓Obesity-induced insulin resistance (↓Type 2 diabetes and obesity)

•

↑G protein-coupled signaling

•

Regulate cellular lipid levels mediated by SREBPs

↑GLUT1 mediated glucose uptake and hypothalamic regulations

•

↑p38- MAPK mediated by PPARγ (↓Vascular calcification)

(↓Diabetes and Alzheimer’s diseases)

•

↑Adiponectin to leptin ratio in circulating blood

↑Lipid transporting vesicles (↑SNARE protein complexes)

•

• • • •

•

↓ERK-1, ERK -2, HIF-1α, PGE-2, MMP-2, VEGF (↓Endothelial

migration and proliferation)

↓CNS Oligodendrocyte damage and subsequent axonal demyelination (↓ MS)

•

↑Poxytrins (↓blood platelet aggregation)

↑Resolvins, protectins, and maresins (↑protection from injury,

•

↑Macrophage clearance (↓MI, CHD)

ischaemia, and inflammation)

•

↓Cholesterol biosynthesis

↓ADHD and DCD

•

↓Cholesterol efflux protein ABCA1

Fig. 5. Role of n−3 FUFAs in (I) resolving inflammation and prevention of infection, (II) cancer prevention, (III) brain development, and (IV) obesity, diabetes, and cardiovascular disease (CVD) prevention. List of Abbreviations: ABCA: ATP-binding cassette transporter A; ADHD: attention deficit hyperactivity; BECs: bronchial epithelial cells; DCD: developmental coordination disorder; ELAM1: endothelial-leukocyte adhesion molecule 1; eIF: eukaryotic Initiation Factor; ERK: extracellular signal-regulated kinase; GLUT: glucose transporter; HIF: hypoxiainducible-factor; IBD: inflammatory bowel disease; ICAM: intercellular adhesion molecule; MAPK: mitogen-activated protein kinase; MI: myocardial infarction; NOD: nucleotide-binding oligomerization domain; proteins; PPAR: peroxisome proliferator-activated receptors; PMN: polymorphonuclear neutrophils; SPM: specialized pro-resolving mediators; SREBPs: sterol regulatory element-binding proteins; TLR: Toll-like receptors; VCAM: vascular cell adhesion molecule; VEGF: vascular endothelial growth factor.

(physiological processes of appetite, pain-sensation, mood, and memory) [1]. In addition to direct involvement of DHA in brain function, several DHA-derived mediators such as neuroprotectins, resolvins, and maresins produced in the brain also play important roles in protection against injury, ischemia, and inflammation [1]. EPA is also beneficial to patients suffering from multiple sclerosis, a chronic inflammatory demyelinating disease of the CNS that can cause neurological disability in young adults. EPA-derived metabolites 18-hydroxyeicosapentaenoic acid (18-HEPE) can promote the regenerative process of remyelination after toxic injury to CNS oligodendrocytes [59]. A large number of epidemiological, laboratory, and randomized placebo-controlled trials have suggested that n−3 PUFA's deficiency can cause mood disorders possibly through increased production of n−6 PUFAs derived pro-inflammatory eicosanoids and cytokines associated with depression [60,61]. There is a negative correlation of n−3 PUFAs intake with depression [61]. These authors have also presented low prevalence rates of depression in areas with high seafood consumption such as in Japan. Controlled trials involving n−3 PUFAs supplementation for treating major depressive disorder and Alzheimer's disease have been discussed [60]. EPA and DHA can work

of high amount of DHA in synaptic signaling sites of brain synaptosomal plasma membranes and synaptic vesicles is evolutionary conserved [57]. The high degree of conformational flexibility due to multiple double bonds is a possible fundamental aspect of diverse biological properties associated with DHA, including cognitive processes [56]. Integration of DHA-phospholipids considerably alters several fundamental properties of membranes, including acyl chain order and fluidity, elastic compressibility, permeability, phase behavior, fusion, flip-flop protein (flippase) activity [56]. Thus, alterations in fatty acid composition of membranes can significantly influence a wide range of brain functions, including maintenance of axons and dendrites, cell shape, lipid raft formation, G protein-coupled signaling (leading to altered gene expression), polarity, neuronal plasticity, dopamine storage, vesicle formation and transport, glucose uptake, and hypothalamic regulations [58]. These alterations are associated with several psychiatric disorders and neurodegenerative diseases, such as axons and dendrites instability associated with Alzheimer's disease, motor system mediated Parkinson's disease, and major depression. It has been suggested that n−3 PUFAs can exert antidepressant effect through several mechanisms, including modulation of the hypothalamic–pituitary–adrenal axis, neuroinflammation, and endocannabinoid metabolism 262

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cholesterol biosynthesis enzymes [including hydroxymethylglutaryl (HMG)-CoA synthase 1, HMG-CoA reductase, farnesyl diphosphate (FPP) synthase, and squalene synthase (SQS)] and post-transcriptional suppression of a cholesterol efflux protein ABCA1 (ATP-binding cassette transporter A1) from the liver [72]. Thus, it has been suggested that n−3 PUFA (ALA) and LC n−3 PUFA (EPA) can be used as natural substance for prevention and treatment of chronic diseases including hypercholesterolemia in humans [72]. LC n−3 and n−6 PUFAs have different regulatory effects on adipogenic and lipogenic genes in adipocytes. In mature 3T3-L1 adipocytes, ARA has a dominant effect over n−3 PUFA on the regulation of lipogenic genes including acetyl-CoA carboxylase 1 and stearoyl-CoA desaturase (SCD1) [73]. This effect might be due to higher accumulation of ARA over n−3 PUFA in mature adipocytes. Thus, increasing the consumption of n−3 PUFA to maintain and regulate adipocytes metabolism appropriately has been recommended. In a 25-year follow-up study on American young adults, intake of LC n−3 PUFAs (0.03–0.40 g/day) from its primary food source (fish) has been found to be inversely associated with the incidence of individual components of metabolic diseases, including blood pressure, fasting glucose, HDL cholesterol, and triglycerides in a dose-dependent manner [74]. An overview of the effect of n−3 PUFAs on blood vessels and blood pressure and their relevance for CVD prevention has been recently presented by Colussi et al. [64]. These authors have reviewed beneficial effects of n−3 PUFAs on endothelium and vascular smooth muscle cells, inflammation and thrombosis, plaque formation and stability, arterial stiffness, blood pressure, and CVD and concluded that there are sufficient evidences to support the role of n−3 PUFAs in decreasing blood pressure in hypertensive patients. Supplementation of n−3 FUFAs is also a promising novel nutritional approach to reduce obesity and associated metabolic disorders. n−3 PUFAs are effective in protecting against obesity by activating brown adipose tissue (BAT) which helps energy expenditure through its specialized thermogenic function [75]. EPA increases thermogenesis through uncoupling protein 1 (UCP-1) to prevent obesity. UCP-1 is a key biomarker for BAT activity. It uncouples (stimulate oxygen consumption without a concomitant increase in ATP production) mitochondrial respiration, allowing heat generation. It also mediates nonshivering thermogenesis (NST) during catecholamine-mediated lipolysis and cold exposure [75]. In addition to the amount n−3 and n−6 PUFA, genetic polymorphism in desaturase and elongase genes can also influence the development of chronic diseases. In a review, Simopoulos [76] has described that single nucleotide polymorphisms (SNPs) in Δ5- and Δ6desaturases (FADS1 and FADS2, respectively) can influence plasma, serum, and membrane phospholipid levels of PUFAs and LC-PUFAs during pregnancy and lactation which may influence infant's intelligence quotient and increase the risk of atopy (genetic tendency to develop allergic diseases) and CHD. At low intakes of EPA and DHA, SNPs at 5-lipoxygenase (5-LO) can increase the risk for CHD whereas SNPs at cyclooxygenase-2 (COX-2) are involved in the pathogenesis of prostate carcinoma. The author has summarized that all sizeable cohort and epidemiological (intervention) studies addressing biological effects of PUFA and LC-PUFAs with consequences of genetic variants in FADS1, FADS2, 5-LOX, and COX-2 should be taken into consideration in the future to determine the precise nutritional requirement for EPA and DHA. Large numbers of experimental studies and randomized clinical trials have provided controversial results regarding the ability of n−3 PUFAs to reduce the risk of CVD. However, a recent study pooling 19 cohort studies with 45,637 individuals from 16 countries, 7973 total CHD, and 2781 fatal CHD has found that concentrations of n−3 biomarkers of ALA, DPA, and DHA (including total plasma, erythrocyte and plasma phospholipids, cholesterol esters, triglycerides, and adipose tissue) are strongly associated with lower risk of fatal CHD across diverse population subgroups, with relative risk of 0.91 for higher

synergistically to reduce depressive scores. However, the optimal ratio of EPA to DHA needs to be investigated by further studies. The high degree of unsaturation and fluidity of membranes mediated by DHA enhances the process of rhodopsin activation in visual signaling and several protein-protein interactions, similar to that in brain and neural functioning [56]. DHA also plays an important role as extra- and intracellular signaling molecules [62]. Epidemiological and intervention studies have linked low plasma and blood DHA levels to increased risk of visual and neurological development in infants and children. They also increase the risk of dementia in older individuals [8]. Supplementation of n−3 and n−6 FAs in children can improve neurodevelopmental difficulties such as attention deficit hyperactivity and developmental coordination disorder [8]. With a double-blind placebo-controlled trial, Johnson et al. [63] have observed that reading ability in n−3 and n−6 fatty acid-treated mainstream schoolchildren is improved, specifically the clinically relevant ‘phonologic decoding time’ and ‘visual analysis time.’ In particular, children with attention difficulties have shown substantial benefits from n−3 PUFAs supplementation. 6.2. PUFAs in CVD and obesity Improved intake of n−3 PUFA is a promising novel nutritional approach to CVD, including coronary artery diseases (CAD) such as angina and myocardial infarction (MI) [6,7]. It is known that n−3 PUFAs can regulate cholesterol levels, adipocytes metabolism, lipogenesis, inflammation, thrombosis, and arterial stiffness, thus potentially minimizing CVD [64,65]. Higher consumption of n−3 PUFAs also provides protection against ventricular arrhythmia (abnormal heart rhythms), a crucial factor responsible for sudden cardiac death after MI [66]. Reduced ratios of n−3 index (phosphatidylinositol and sphingomyelin phospholipids) in erythrocytes can lead to higher production of pro-inflammatory eicosanoids than anti-inflammatory eicosanoids as a potential contributor to depressive symptoms in patients with CAD [67]. These authors have suggested that n−3 index in erythrocytes can be used as a diagnostic biomarker for disease etiopathology. From a 16year follow-up study, Hu et al. [68] have observed an inverse relationship between fish consumption and risk of coronary heart disease (CHD), with relative risk of 0.79 in women consuming fish 1 to 3 times per month, 0.71 for those who consume fish once per week, 0.69 for those who consume fish 2 to 4 times per week, and 0.66 for those who consume 5 or more times per week. Increasing fish consumption or fishoil supplementation can also reduce mortality of patients with preexisting CHD. Diets high in SFAs often increase circulating cholesterol levels (plasma cholesterol) including LDL, a potential risk factor for CHD. Thus, dietary intervention has been the focus in many studies to reduce plasma cholesterol levels. In a study on healthy male and female normolipidemic human subjects, consumption of diets with a low PUFAs/ SFAs ratio of 0.5:1 has been shown to be able to reduce plasma total and LDL cholesterol concentrations without changing HDL-cholesterol or triacylglycerol concentrations independent of shifts in cholesterol absorption or synthesis [69]. In spite of the association between SFAs and CVD and elevated blood lipid levels, SFA increases plasma levels of TAGs only when diet is deficient in n−3 PUFAs [70]. However, in subjects with adequate n−3 index, saturated fat-rich diet does not significantly affect LDL particle concentration or LDL cholesterol (LDLC) levels, although diet rich in n−6 PUFAs can decrease LDL particle concentration (−8%) and LDL-C level (−8%). These authors have summarized that sufficient intake of n−3 PUFAs during pre-supplementation period can significantly influence the effect of SFAs and n−6 PUFAs on lipoprotein profile [70]. EPA (n−3 PUFA) is well-known for its hypotriglycemic effect. Most results are obtained from combined effects of inhibition of lipogenesis and prompt fatty acid oxidation in the liver [71]. In contrast, plasma cholesterol-lowering activities of EPA are due to suppression of 263

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food frequency questionnaires (FFQ) may also be responsible for inconsistent results due to recall error. This can be minimized by using nutrient intake or nutrient status biomarkers. Selection of biomarker is also crucial to obtain association between n−3 intake and health or disease. Del Gobbo et al. [7] have suggested that phospholipids or total plasma is the most suitable biomarker to assess the protective effect of n−3 PUFAs exposure against incidental CHD.

concentration of ALA, 0.90 for higher concentration of DPA, and 0.90 for higher concentration of DHA [7]. Across quintiles, lower risk of nonfatal MI was evident with higher levels of EPA and ALA and lower risk of fatal CHD was evident with higher levels of DPA and DHA. These authors have concluded that biomarker concentrations of seafood (EPA, DPA, and DHA) and plant-derived n−3 FAs (ALA) are associated with significantly lower incidence of fatal CHD on the basis of available studies from global populations. Authors have also suggested that phospholipids or total plasma levels can be used as the most suitable biomarker for LC n−3 PUFAs exposure.

6.4. PUFAs in bone health Nutrients beyond calcium, vitamin D, quality, and quantity of dietary n−3 LC-PUFAs may also have consequences on bone health. They have been found to be beneficial for treatment and prevention of osteoporosis [81]. FAs can influence bone health by mediating calcium absorption, hormonal changes, gene expression, lipid peroxidation, and eicosanoid production. For instance, ALA-rich diets can significantly decrease N-terminal telopeptide levels (a bone resorption marker) and maintain bone-specific alkaline phosphatase activity, thus regulating bone formation and mineralization [82]. Additionally, n−3 FAs can improve body mineral density (BMD) by increasing Ca+2 absorption, decreasing urinary Ca+2 excretion, and decreasing necrosis factor α (TNF-α) by activating nuclear factor-kappa β (NF-κB) ligand on T cells [81]. Since TNF-αis involved in bone destruction in rheumatoid arthritis, n−3 PUFAs that can reduce the production of prostaglandin E2 (a potent stimulator of bone resorption) can also be used as an antiosteoporosis therapy.

6.3. PUFAs in cancer A large number of in vitro and animal studies have established that n−3 and n−6 PUFAs have contrasting effects on cancer development. n−3 LC-FUFAs such as EPA and DHA can suppress tumor carcinogenesis whereas n−6 PUFA can promote cancer development [77,78].The precise mechanism of the anticancer activity of n−3 LC-FUFAs has not been well understood yet. The mechanisms suggested are: (i) They might act through cellular signaling mediators, including protein kinase C, mitogen-activated protein kinase (MAPK), and NF-κB, (ii) they might act directly as ligands for nuclear receptors such as peroxisome proliferators-activated receptors (PPARs) and retinoid X receptor alpha, (iii) they might control intracellular homeostasis through regulating Ca++ channels on plasma membrane to activate eIF2α kinase which can down-regulate oncogenes and G1 cyclins, (iv) they might alter lipid composition of the plasma membrane which can affect membrane fluidity and interaction between T cells and antigen-presenting cells (APCs), and (v) they might regulate non-enzymatic lipid peroxidation which induces apoptosis in tumor cells [4]. The most widely studied cariogenic effects of n−6 LC-PUFAs are their selective production of pro-inflammatory eicosanoids. Thus, a low ratio of dietary n−6/n−3 PUFAs is associated with reduced risk of several types of carcinogenesis. However, this depends on numerous factors, including race/ethnicity, the source of n−3 PUFAs (fish oils, seed oils, purified PUFAs), and genetic differences in enzymes responsible for lipid metabolism (polymorphism in modifier genes) [4]. In race/ethnicity-specific analyses, increasing dietary ratio of n−6/n−3 FAs is correlated with higher prostate cancer risk among white men, but not among black men [79]. Such racial difference might be due to genetic differences in a key enzyme involved in fatty acid metabolism, including COX and LOX [76]. Several epidemiological studies focusing on cardioprotective and anticancer properties of n−3 PUFAs have reported inconsistent results. Many studies have reported a strong inverse association between the intake of n−3 PUFAs and the risk of CVD and colon, breast, and prostate cancer. However, some studies reported that the intake of n−3 PUFAs has no effect or very poor effect on the risk of CVD or cancer [80]. A large number of factors might be responsible for these inconsistent results. In some studies, the actual intake in n−3 PUFAs might be too low to show a significant protective effect. The protective effect of n−3 PUFAs may be alleviated by other dietary components such as high contents of n−6 PUFAs. Thus, the ratio of n−6 to n−3 is more crucial than the absolute amount of n−3 PUFAs. Lower ratio of n−6 to n−3 (< 5) is effective against chronic diseases. Second, SNPs in modifier genes may influence the metabolism of n−6 and n−3 PUFAs. For instance, COX and LOX families of enzymes can metabolize both n−6 and n−3 PUFAs to eicosanoids with contrasting effects (pro-inflammatory and anti-inflammatory effects, respectively) that could modulate cancer risk. In addition to SNPs, other individual parameters such as gender, ethnicity, the presence of other diseases (e.g., diabetes), and medication (e.g., aspirin, statin) may influence the outcome. Thus, genetic factors and individual parameters should be considered in order to achieve consistent results. Finally, the source of n−3 PUFAs (e.g., ALA, EPA or DHA) and its nature (triglycerides, phospholipids, or esters) also play important roles in bioaccessibility and bioavailability. Self-reported measures of dietary n−3 intake generally derived from

7. Summary A wealth of prospective cohort studies and randomized controlled trials support the idea that populations in regions that consume a ratio of n−6 to n−3 FAs closer to 1:1 have fewer chronic diseases than those in areas that consume mostly n−6 FAs with Western diets having ratio of n−6 to n−3 FAs at 15/1 to 16.7/1. Oily cold-water fishes are rich natural source of LC n−3 PUFAs. In recent years, dietary supplements of n−3 LC-PUFAs in the form of triglycerides (e.g., fish oil), free fatty acid, ethyl esters, or phospholipids (e.g., Krill oil) are popular. They have distinct levels of bioavailability and biological activities in animals. In the future, these factors need to be investigated in detail. Enhancement of n−3 FAs in animal products by feeding n−3 FAs rich diets or by genetic engineering fatty acid biosynthetic pathways has shown potential to improve contents of n−3 PUFAs in the diet. However, these strategies need to be fine-tuned. In addition, the approval and releasing of genetically modified crops are challenging due to social concerns. The conversion of LA and ALA to respective LC-PUFAs depends on several dietary and genetic factors, including the ratio of LA and ALA in the diet, deficiency of other nutrients, gender difference, and polymorphisms in desaturases and elongases. These factors need to be considered in dietary recommendations of PUFAs. In addition to the absolute content of particular FAs, emphasis should be given to the ratio of n−6 and n−3 PUFAs when assessing the relationship between PUFAs intake and risk of chronic diseases. It is evident that difference in other dietary nutrients (e.g., vitamin A) may affect the biosynthesis and membrane incorporation of DHA. However, such factors have not been well studied. Hence, further investigation is needed to unravel the mechanism by which vitamin A and other nutrients influence membrane DHA and other LC-PUFAs. Maternal intake of PUFAs during pregnancy and lactation also affects brain and retinal development of infants. Thus, balanced intake of n−6 and n−3 PUFAs is very crucial for homeostasis and proper development of developing fetus and children. The recommended intake (RI) of n−3 FUFAs (250 mg to 1000 mg/day of EPA and DHA) from natural diet or dietary supplement has been suggested by different agencies to maintain body homeostasis and prevent chronic diseases. An RI of 1000 to 2000 mg/day of EPA and DHA has been advised to 264

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cure or minimize the impact of chronic diseases. Significant variation existing in recommended dietary intakes has to be minimized to obtain precise levels. Several mechanisms by which n−3 FUFAs maintain body homeostasis and provide protection against several chronic and metabolic disease, including cardiovascular, diabetes, cancer, obesity, neurodegenerative, and vision-related diseases have been proposed, including the following: (1) They can enhance the production of anti-inflammatory eicosanoids, including lipoxins, resolvins, protectins, and maresins that can enhance phagocytosis and resolution of inflammation; (2) they can inhibit the production of adhesion molecules (ICAM1, VCAM-1, ELAM-1) mediated by peroxysome proliferator-activated receptors (PPARα and PPARγ); (3) they can limit the production and activity of inflammatory mediators, including protein kinases (JNK, MAPK, p38), nuclear factor-κB, chemokines, cytokines (TNFα, TNF-1β, IL-1, IL-1, IL-6, IL-8, MCP-1, etc.), and angiogenic growth factors (VEGF); (4) they can inhibit sterol regulatory element binding protein 1c (SREBP-1c) nuclear factor which mediates lipid degradation and reduces lipid biosynthesis; and (5) they can improve glucose uptake and hypothalamic regulation. The potential relevance of eicosanoids signaling in inflammatory, cancer, and CVD has been established. Further understanding of singling pathways might clarify benefits of n−3 PUFAs. Moreover, it can provide a rationale to develop novel anti-inflammatory therapeutic approaches for these diseases.

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