PUFAs Structure and Role: Comparison
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Please note this is a comparison between Version 2 by Sirius Huang and Version 1 by Ioannis Patrikios.

The beneficial effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) polyunsaturated fatty acids (omega-3 PUFAs) are nowadays highlighted by a plethora of studies. They play a role in suppression of inflammation, gene expression, cellular membrane fluidity/permeability, immune functionality and intracellular/exocellular signaling.

  • EPA/DHA/LA/GLA
  • omega-3
  • omega-6
  • PUFA
  • polyunsaturated

1. The Leading Role of Lipids

Lipids are considered a heterogenous group of molecules that have hydrophobicity as a common property. Their structure ranges from simple short hydrocarbon chains to more complex chains, including triacylglycerols, sterols, sphingolipids, and phospholipids. Based on their length, degree of saturation, and hydroxylation, their biophysical properties are determined [7][1].
They are implicated in the regulation of the expression of transcription factors and several metabolic processes, such as fatty acid synthesis, oxidation, insulin sensitivity, and central nervous system function [8][2]. Fatty acids are divided into different categories that include saturated, monounsaturated, polyunsaturated, cis and trans fats [9][3].
Fatty acids in general are major components of all forms of lipids and, together with cholesterol and coalesce in the cell membrane, form the lipid bilayer of cells and organelles [10][4]. They are derived either de novo or from exogenous sources. In the human body, specific fatty acids can be synthesized from glucose or through metabolism of different lipid precursors. Different food sources contain different amounts and types of fatty acids that can be further esterified and/or metabolized into other forms of fatty acids or lipids. Cooking methods can affect the fatty acid content of various foods to a degree, of even becoming dangerous for health, due to the formation of polymers with hemagglutinin characteristics, saturated lipids, and fatty acids in trans stereochemical structure [11][5]. Different cells have different fatty acid composition that influences the membrane’s fluidity/permeability, as well as the function and movement of membranous proteins [12][6]. Membrane phospholipid fatty acids most frequently contain 12 to 24 carbon atoms forming hydrocarbon chains [13][7].

2. PUFAs Structure and Role

PUFAs are a type of fatty acids that contain two or more double bonds within their hydrocarbon chain. PUFAs can be classified based on the position of the initial double bond in relation to the omega methyl group located at the end. Omega-3 or omega-6 PUFAs are distinguished by the presence of a double bond positioned three or six atoms away from the omega terminus carbon, respectively. These PUFAs exhibit amphipathic characteristics due to the hydrophobic lipid tails and the hydrophilic phosphate-rich heads on the outer side [14,15][8][9].
Consumption of PUFAs results in their penetration and incorporation into the cell membranes from where they can exert actions on cell functions. More specifically, apart from maintaining cell membrane fluidity, they affect many functions of the cells including decreasing secretion of cytokines by monocytes, decreasing susceptibility to ventricular rhythm disorders, affecting specific cellular movement and translocation, and inhibiting platelet aggregation [16,17][10][11].
The human body can produce limited amounts of LA and a-linoleic acid (ALA) which are the precursor molecules for the production of any other form of PUFAs and therefore are called essential fatty acids. For that reason, external supplementation is needed to meet the demand. It has been clearly reported that essential fatty acid shortage can potentially contribute to dermatitis, renal hypertension, mitochondrial activity disorders, cardiovascular diseases, type 2 diabetes, impaired brain development, arthritis, depression, and decreased body resistance to infection [16,17][10][11].
Some of these defects may be due to low intake of omega-3/omega-6 PUFAs like alpha-linolenic acid (omega-3) and/or linoleic acid (omega-6). They might also be in relation to the metabolic products of LA and ALA, including the long-chain omega-6 PUFAs arachidonic acid (AA, 20:4 omega-6) and the long-chain omega-3 PUFAs eicosapentaenoic acid (EPA, 20:5 omega-3) and docosahexaenoic acid (DHA, 22:6 omega-3) [16][10].
All aforementioned essential molecules play an important role in mediating inflammatory responses and exert a wide spectrum of biologic activity in different body systems. The three major subtypes of eicosanoids and their major biologic actions are summarized in Figure 1.
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Figure 1. Pathway of biosynthesis of eicosanoids from arachidonic acid. Eicosanoids are not stored within cells and are synthesized as needed when their biosynthesis is activated by trauma/inflammation or cytokines which activate phospholipase A2 (PLA2). Fatty acids that are cleaved by PLA2 from cell membranes are then oxygenated by one of three different families of enzymes to produce eicosanoids [18][12].
As previously mentioned, inflammation is involved in neurodegenerative disorders and cognitive decline. The relationship between inflammation and oxidative stress is bidirectional: oxidative stress induces inflammation and inflammation induces oxidative stress (Figure 2). Hence, agents that act to reduce oxidative stress can also be considered as anti-inflammatory.
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Figure 2. The bidirectional links between inflammation and oxidative stress. Reactive oxygen species (ROS) can act as inflammatory trigger initiating inflammation. On the other hand, inflammation induces oxidative stress. IkB, inhibitory subunit of NFkB; MAPK, mitogen-activated protein kinase; NFkB, nuclear factor kappa-light-chain-enhancer of activated B cells; P, phosphate; ROS, reactive oxygen species [19][13].
Resolution of inflammation has always been viewed as a passive process, occurring because of the withdrawal of proinflammatory signals which further includes lipid mediators, such as leukotrienes and prostaglandins, as shown earlier [20][14]. Recently, it has been established that inflammation resolution is an active process with a distinct set of chemical mediators, including PUFAs. Molecules, such as resolvins and protectins, are nowadays identified as molecules that are generated from omega-3 PUFA precursors and can orchestrate the timely resolution of inflammation in model systems [20][14].

2.1. Omega-3 and Omega-6 PUFAs

α-linolenic acid (ALA, 18:3 omega-3), eicosapentaenoic acid (EPA, 20:5 omega-3) and docosahexaenoic acid (DHA, 22:6 omega-3) are all omega-3 fatty acids whilst linoleic acid (LA, 18:2 omega-6) and arachidonic acid (AA, 20:4 omega-6) belong to omega-6 fatty acids (see Figure 3). Although the human body cannot synthesize them, mainly because of the deficiency of one of the conversion enzymes, the omega-3-desaturase, it is able to metabolize them [21][15].
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Figure 3.
Space filling chemical structures of omega-3 and omega-6 PUFAs.
Through elongation stages, ALA is metabolized to EPA and DHA by two specific enzymes, Δ6 desaturase and Δ5 desaturase, whilst LA is metabolized to AA. EPA and ALA both compete for the same enzyme system, therefore, high background n-6 PUFA intake reduce interconversion of n-3 PUFAs (Figure 4).
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Figure 4. Pathway of metabolic interconversion of omega-6 and omega-3 polyunsaturated fatty acids. LA and ALA are the parent PUFAs for omega-6 and omega-3, respectively. Abbreviation used: Δ, delta [22][16].
As previously mentioned, AA is known as the precursor of proinflammatory mediators including prostaglandins and leukotrienes which promote inflammation [23][17]. DHA and AA are the most important PUFAs in the human brain with DHA being the major PUFA that has a prominent role in brain development. More specifically, more than 90% of the omega-3 PUFAs and 20% of the total brain lipids consists of DHA. DHA is incorporated in phosphatidylcholine, phosphatidylserine and at synaptic terminals and endoplasmic reticula. Among DHA’s actions, modulation of cellular properties, release of neurotransmitters and neuronal growth and gene expression are noted. Although several questions remain partially answered, this molecule is very promising and further research could identify a solid correlation between high DHA concentrations and neuroprotection [24][18].

2.2. PUFAs Transportation to the Brain

Research conducted in laboratory settings and living organisms has provided evidence that dietary intake of EPA, DHA, LA, and GLA can play a role in influencing and regulating various intricate networks of events and pathways involved in brain pathophysiology. The composition of fatty acids in the brain’s membranes can be altered through dietary supplementation, although this process has been observed to be influenced by age (taking longer time in adults compared to developing brains) and possibly influenced by the quantity of PUFAs consumed or supplemented. Both human and animal studies have demonstrated that diets rich in DHA and EPA can elevate the proportion of these PUFAs in the membranes of inflammatory cells while simultaneously decreasing the AA levels [16][10].
Oral supplementation increases the content of omega-3 PUFAs in the cerebrospinal fluid, although efficient passage through the blood–brain barrier requires a carrier particle. DHA needs 1-lyso, 2-docosahexaenoyl-glycerophosphocholine (LysoPC-DHA), which is brain specific to be transported to the brain. Carriers able to transport DHA to the brain with better properties are further studied and research is promising [25][19]. An example of a potential carrier with superior characteristics is AceDoPC (1-acetyl,2-docosahexaenoyl-glycerophosphocholine). This is a structured glycerophospholipid that facilitates the transport of DHA and has been shown to be associated with neuroprotective properties [26][20].

2.3. Omega-3 and Omega-6 Dietary Sources

As omega-3 and omega-6 are considered essential fatty acids, diet has a vital role in providing them [27][21]. There are various sources of long-chain PUFAs, both aquatic as well as animal. Oily fish of cold water is considered as an excellent source of long-chain omega-3 PUFAs, predominantly EPA and DHA. Fatty acids from animal sources, such as beef, lamb, pork, poultry, and dairy products are influenced by the diet and the digestive system of each animal. More specifically, muscle and adipose tissue of meat are rich in ALA, EPA, DPA and DHA [27][21]. DHA is found in high concentrations (0.7%) in egg yolk and its concentration can even increase when a chicken’s diet is supplemented with fish oils. Important plant sources of ALA include black raspberry seed oil which reaches a concentration of 35% as well as cranberry, basil seed oil, chia seed oil, walnut seed oil and flaxseed oil. LA is found in high concentrations in safflower and corn oils which can be further metabolized to other omega-6 fatty acids [27][21].

2.4. Ratio of Omega-3 to Omega-6 PUFAs

Several studies suggest that the ratio of omega-3/omega-6 should be 1:1, but in the industrial countries the ratio is about 1:20 due to the high quantities of omega-6 in the everyday diet, fast foods and especially AA. An unbalanced omega-3/omega-6 ratio compromises, among others, the brain’s cytoarchitecture and functioning, cellular integrity and the physiological status of the immune cells as well [28][22].
A diet high in AA has a negative impact on health as it promotes the pathogenesis of several diseases as previously mentioned. In contrast, it is supported that omega-3 PUFAs, are able to affect neuronal transmission by changing the phospholipid composition and can positively contribute on the fluidity of the central nervous system cellular membranes [12][6]. Therefore, the strong relationship between PUFAs’ status and brain functions, such as neurotransmission and behavior are highlighted, whilst a diet poor in n-3 PUFAs is considered detrimental to health [29][23].
There is accumulating scientific evidence on the possible efficacy of PUFAs supplementation in neurodegenerative disorders. Although dietary recommendations are far from being accepted as treatment for neurodegenerative disorders, they may be able to alleviate some of the symptoms and most importantly slow cognitive and physical decline which have the highest impact on the quality of life [30][24].
Omega-3 PUFAs are considered the most prescribed supplements and it is predicted that their use will rise by 6.5% from 2023 to 2032; their market segment is estimated to exceed 4.5 billion dollars by 2032 [31][25]. As omega-3 fatty acids are supplements that do not need testing and approval by official approval bodies, routine clinical practice in diseases should provide evidence for their role [30][24].

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