LONG CHAIN FATTY ACIDS (PUFAs)


Fats are complex molecules composed of fatty acids (chains of carbon and hydrogen atoms, with a carboxylic acid group at one end) and glycerol. The body needs fats for growth and energy. Fats are chemically described as either unsaturated, monounsaturated or polyunsaturated. The saturated fatty acids elevate serum cholesterol and low density lipoprotein (LDL) levels. Monounsaturated fatty acids (MUFA) raise high density lipoproteins (HDL). Polyunsaturated fatty acids (PUFA) moderately reduce serum cholesterol and LDL levels. (1)

Fat is the most energy dense of all the macronutrients with 1g providing 9kcal. However, the constituent parts of fat, fatty acids, are required by the body for many other functions than as simply an energy source and there is an increasing awareness of the potential health benefits of specific types of fatty acids. Fat is found in most food groups and foods containing fat generally provide a range of different fatty acids, both saturated and unsaturated fatty acids. In humans, the essential fatty acids are the omega 3 polyunsaturated fatty acid α-linolenic acid(ALA) and the omega 6 polyunsaturated fatty acid linoleic acid (LA). Docosahexaenoic acid (DHA) is an omega-3 (n-3) long-chain (LC) polyunsaturated fatty acid (PUFA) that is a primary structural component of the human brain, testes and retina. It is derived from LA and arachidonic acid (AA)

Long Chain (LC) PUFA : Linoleic acid (LA) and alpha linolenic acid (ALA) are long chain PUFA that are essential fatty acids as they cannot be synthesized in the body and must be consumed in the diet. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (omega 3 fatty acid), which are fatty acids essential for brain development, are synthesized from ALA whereas arachidonic acid (ARA) which is an omega 6 fatty acid is formed from LA. Both omega 6 (n-6)and omega 3 (n-3) essential fatty acids compete for the same enzymes and have different biological roles, the balance between the n-6 and the n-3 fatty acids in the diet is of considerable importance.

Eicosanoids Synthesis :
Linoleic acid and α-linolenic acid are substrates for the synthesis of physiological regulators called eicosanoids. Eicosanoids include prostaglandins, prostacyclins, thromboxanes, and leukotrienes. For each, there are two or three separate series. These are potent mediators of many biochemical processes and play key roles in the regulation of blood clots, blood pressure, blood lipid levels, immune function, inflammation, pain and fever, and reproduction. The omega-6 eicosanoids (derived from LA) are generally pro-inflammatory. Consuming large amount of linoleic acid increases the quantity of arachidonic acid(AA) in cell membranes. Upon activation, in a variety of cells, arachidonic acid is converted to eicosanoids of the 2 series and leukotrienes of the 4 series. However, dietary α- linolenic acid is converted to Eicosapentaenoic acid (EPA) in the membrane, and when cells are activated, EPA is converted to eicosanoids of the 3 series and leukotrienes of the 5 series.

Role of long chain PUFA : These long chain PUFAs have critical roles in the membrane phospholipids and are structural and functional components of cell membranes. These fatty acids are indispensable for cell membrane synthesis. The brain, retina and others neural tissues are particularly rich in long chain PUFA (2,3). n-3 fatty acids also play a central role in the functioning of the brain and central nervous system. Together with n-6 fatty acids, they are not only involved in the development and maturation of neuronal structures, but are essential throughout the entire life span for maintaining normal brain and nervous system function (4). Both DHA and ARA are concentrated in the membrane lipids of gray matter and in the visual elements of the retina (5). EPA is not stored in significant quantity in the brain or retina. EPA may play a more important role in cardiovascular and immunological health. (6)

These fatty acids serve as specific precursors for eicosanoids, which exert hormonal and immunological activity. n-6 PUFA are the precursors for pro-inflammatory molecules-the molecules that promote and maintain inflammatory reactions whereas n-3 fats, in contrast, are the precursors for anti-inflammatory molecules (2,3).

In particular, the vascular-protective effects of long-chain n-3 fatty acids are well documented. EPA und DHA are known to affect the lipid profile, vascular tone and blood coagulation. (4)

DHA and other LC-PUFA and physiological functions in the nervous system :
LC-PUFAs play a central role in the normal functioning of the brain and nervous system. As structural components of neuronal cell membranes, LC-PUFAs—in particular AA and DHA—have a considerable influence on signal transduction. Studies with rats, for example, demonstrated that chronic n-3 fatty acid deficiency induces abnormalities in dopaminergic and serotonergic neurotransmission systems, which are closely involved in the modulation of attention, motivation and emotion. (4) The exact mechanisms explaining these effects are not completely understood. However, these studies suggest that an increasing proportion in favour of n-3 fatty acids modifies the physical properties of the neuronal cell membranes, which influences the proteins (receptors, transporters) enclosed in the membrane. (4) LC-PUFAs are able to influence cellular signal processes and transmissions, for example by changing the binding or release of neurotransmitters. (4) Another mechanism by which LC-PUFAs—especially n-3 fatty acids—exert their function in the nervous system is their potential to regulate brain gene expression.

Immune Function :
A deficiency of either n-6 or n-3 essential fatty acids is associated with a reduced immune function. Amongst the fatty acids, the n-3 fatty acids possess the most potent immunomodulatory activities, and amongst the n-3 fatty acids, those from fish oil (EPA and DHA) are more potent than a-linolenic acid. In particular, it has been demonstrated that feeding DHA and eicosapentaenoic acid (EPA) decreases the rate of infections and improves outcome (i.e., reduced complications, length of stay, hospital cost) in immunosuppressed patients.

Preterm and neonates :
DHA is the most abundant PUFA in the central nervous system, being particularly concentrated in synaptic plasma membranes [7,8] and in photoreceptor cells [9]. It is critical that the correct acquisition of n-3 and n-6 fatty acids occurs during embryogenesis and early postnatal stages of development. In humans this process takes place during the last trimester and first 6–10 months after birth [10,11]. The rapid accumulation of DHA is directly related to its crucial need for nor mal neurological and visual development [12]. n-3 deficiency is associated with biochemical changes in brain and retina including decreased DHA, altered enzymatic activities depressed learning ability, and disturbed behavior and water intake [13,14] optimal neurological and visual development [12].

Cardiovascular disease and dietary plasma lipid levels :
Cardiovascular disease (CVD) in general and coronary heart disease (CHD) in particular, is the leading cause of death in industrialized countries. The relationship between dietary n3 fatty acids, particularly eicosapentaenoic acid( EPA) and docosahexaenoic acid,( DHA), and risk of developing CVD began to emerge in the late 1970s [15,16]. Some of the potential mechanisms for the cardioprotective effect of n3 fatty acids include antiarrhythmic, anti-inflammatory, hypotensive, and hypotriglyceridemic effects [17]. Studies using relatively high doses of fish oil indicated that the most consistent effect on plasma markers of cardiovascular disease risk is a decrease in triacylglycerol (TAG) levels [17]. This effect is dose-dependent and is influenced by the baseline plasma TAG level of the subjects. Both fish and vegetable oil consumption increases EPA and DPA n-3 content in serum, platelet, and RBC. Studies in humans demonstrate that ALA is rapidly incorporated into lipoproteins within 3 h after ALA consumption and consequently plasma ALA, EPA and DPA concentrations are elevated after consumption of ALA-enriched sources.

ALA - antiarrhythmic properties :
The antiarrhythmic properties of fish oils were first shown in rats, non-human primates and dogs. The mechanism for the antiarrhythmic effects probably involves the modification ion channels currents by the incorporation of these polyunsaturated fatty acids into the cardio myocytes membrane phospholipid [18–20].

ALA - anti-inflammatory properties :
Inflammation is the cell physiological response to exposure to certain substances released, predominantly, by activated leukocytes. This response usually consists in the reddening and swelling of the targeted area and it is mediated by at least two different groups of biomolecules, the n6 eicosanoids and the cytokines. The n-6 eicosanoids are biosynthetically derived from ARA. One of the most common pharmacological approaches to treat inflammation is to inhibit the biosynthesis of n-6 eicosanoids. This could be achieved by providing COX1/2 inhibitors, e.g. aspirin, or by increasing n3 fatty acid content, particularly EPA and DHA [21]. In turn, n-3 enriched diets can also suppress production of cytokines.

Sources of dietary unsaturated fatty acids :
A good dietary source useful for increasing n3 fatty acid consumption is a greater consumption of vegetable derived n-3 fatty acids. There are only three major commercial sources that have significant amounts of ALA: Linum usitatissimum, linseed or flaxseed oil (53% ALA); Brassica spp. Canola or rapeseed oil (9% ALA) and Glycine max, soybean oil (7% ALA) [1]. Perilla oil, Perilla frutescens, also contains a high percentage in ALA (approx. 60%) although its consumption is restricted to Asia, In plants, ALA is found in leaves, mainly in glycolipids, and as tri acyl glycerol (TAG) in certain seed oils (rapeseed, flaxseed, perilla seed, chia seed), beans (soybeans, navy beans) and nuts (walnuts).

Dietary Intake of DHA, EPA : The ratio of LA to ALA in the diet should be between 5:1 and 10:1. However a typical diet has a ratio of 25:1. Thus, it is important to decrease the amount of n-6 fatty acids in the diet, while increasing the amount of n-3 fatty acids like EPA, DHA, and ALA. This can be accomplished by reducing consumption of meats, dairy products, and refined foods, while increasing consumption of the n-3 rich foods such as flaxseed oil, walnuts, and leafy green vegetables. (2,3). During early life, there is limited metabolic capacity to convert ALA to DHA. Prior to birth, the DHA and ARA required for fetal development are provided by placental transfer. Thereafter, long chain- PUFAs are provided in breast milk. With the introduction of weaning foods, the child shifts gradually from dependence on human milk to complete dependence on a diet of table foods often low in long chain PUFA. After weaning, the child’s diet varies considerably depending on food choices made by the parent/caretaker. Without dietary DHA, blood levels of DHA in children aged 18–60 months are low. (6) In infancy and early childhood, DHA should be acquired from dietary sources to maintain optimal health. (7) Consequently, it is not surprising that a lack of n-3 fatty acids, or an imbalance between n-3 and n-6 fatty acids, is associated with a number of behavioural abnormalities, as well as neurological and psychiatric disorders in both children and adults. Corresponding associations can be found with attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders, as well as with unipolar and bipolar disorders.

Etiology of primary and secondary essential fatty acid deficiency in human beings :
- Chronic malnutrition, especially in children
- Long-term fat-free total parental nutrition (TPN)
- Various fat malabsorption conditions
- Sjogren–Larsson syndrome
- Acrodermatitis enteropathica
- End-stage liver disease

Clinical manifestations of essential fatty acid deficiency in human beings :
- Dermatitis; dry, scaly skin; impetigo; eczema; generalized erythema
- Coarse, sparse hair
- Increased frequency of stools
- Decreased growth rate
- Cellular hyperproliferation in skin, alimentary tract, and urinary tract
- Possible immune impairment
- Slow wound repair
- Slower early learning behaviour
- Mental retardation in human genetic defects involving desaturases and elongases

Conclusion :
LC-PUFAs play a central role in the normal development and functioning of the brain and central nervous system. DHA and AA, in particular, are involved in numerous neuronal processes. Deficiencies and imbalances of these nutrients, not only during the developmental phase but throughout the whole life span, have significant effects on brain function. An adequate supply of long-chain n-3 fatty acids, such as DHA in particular, is therefore indispensable for normal brain development.

References :
1. Fats oils in human nutrition. Available at URL: http://www.fao.org/docrep/v4700e/V4700E0d.htm. Accessed on 17th September 2010
2. ISSFAL: 2009, January, ISSFAL Official Statement Number 5 "α-Linolenic Acid Supplementation and Conversion to n-3 Long Chain Polyunsaturated Fatty Acids in Humans.
3. Docosahexaenoic acid - Wikipedia. Available at URL http://en.wikipedia.org. Accessed on 25th November 2009.
4. Schuchardt JP, Huss M, Stauss-Grabo M, Hahn A. Significance of long-chain polyunsaturated fatty acids (PUFAs) for the development and behaviour of children. Eur J Pediatr. 2010;169:149-64.
5. Innis M. Dietary omega 3 fatty acids and the developing brain, Brain Res. 2008; 1237: 35–43
6. Ryan AS, Astwood JD, Gautier S, Kuratko CN, Nelson EB, Salem N Jr. Effects of long-chain polyunsaturated fatty acid supplementation on neurodevelopment in childhood: a review of human studies. Prostaglandins Leukot Essent Fatty Acids. 2010; 82: 305-314
7. Singh M. Essential fatty acids, DHA and human brain. Indian J Pediatr. 2005; 72: 239-242
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