- Open Access
Can essential fatty acids reduce the burden of disease(s)?
© Das; licensee BioMed Central Ltd. 2008
- Received: 06 March 2008
- Accepted: 18 March 2008
- Published: 18 March 2008
Coronary heart disease, stroke, diabetes mellitus, hypertension, cancer, depression schizophrenia, Alzheimer's disease, and collagen vascular diseases are low-grade systemic inflammatory conditions that are a severe burden on health care resources. Essential fatty acids (EFAs) and their metabolites: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), gamma-linolenic acid (GLA), dihomo-gamma-linolenic acid (DGLA), and arachidonic acid (AA) and their products: prostaglandin E1, prostacyclin, lipoxins, resolvins, and protectins suppress inflammation, augment healing, and are of benefit in the prevention and management of these conditions. Hence, supplementation of EFAs could reduce burden of these disease(s).
- Arachidonic Acid
- Essential Fatty Acid
- Collagen Vascular Disease
- Beneficial Metabolite
Coronary heart disease (CHD), stroke, diabetes mellitus, hypertension, cancer, depression, schizophrenia, Alzheimer's disease, and collagen vascular diseases are a severe burden on the health care system throughout the world . The major determinants of these chronic diseases are tobacco smoking, inadequate physical activity, unhealthy diets, overweight/obesity, suboptimal levels of blood pressure, cholesterol, and plasma glucose [2–4]. It was estimated that a multidrug regimen comprising of a statin, aspirin, and two blood-pressure lowering medicines reduces about 17.9 million deaths from cardiovascular diseases . But, any strategy that prevents stroke, cancer and other chronic diseases in addition to cardiovascular diseases is expected to reduce the burden of chronic diseases substantially. Low-grade systemic inflammation is one of the characteristic features of CHD, stroke, diabetes mellitus, hypertension, cancer, depression schizophrenia, Alzheimer's disease, and collagen vascular diseases implying that prevention or suppression of inflammation reduces burden of these diseases.
Plasma C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), markers of inflammation, levels are elevated in subjects with obesity, insulin resistance, essential hypertension, type 2 diabetes, and CHD [5–10], suggesting that low-grade systemic inflammation occurs in them. Alzheimer's disease, depression, and schizophrenia are also low-grade systemic inflammatory conditions since, elevated levels of pro-inflammatory cytokines occurs in the plasma and brains of these patients [11, 12].
Chronic inflammation is a major causative factor of human malignancies. Pro-inflammatory cytokines influence tumor microenvironment and promote cell growth and survival and angiogenesis such that tumor cell growth is facilitated. Thus, immune system activation could be a double edged sword: immune surveillance may check tumor development whereas aberrant immune activation promotes malignant growth [13, 14].
Most of the PGs, TXs, and LTs have pro-inflammatory actions. AA, EPA and DHA also give rise to anti-inflammatory molecules: lipoxins (LXs), resolvins, and protectins (such as neuroprotectin D1). Thus, PUFAs form precursors to both pro- and anti-inflammatory molecules and the balance between these mutually antagonistic compounds could determine the final outcome of the disease process (see Figure 1). In addition, nitration of unsaturated fatty acids occurs leading to the formation of nitrolipids that stimulate smooth muscle relaxation, block platelet activation, inhibit human neutrophil functions and suppress inflammation [15, 16]. These studies suggest that PUFAs have important actions not only by themselves but also by giving raise to various biologically active compounds.
EFAs/PUFAs play a significant role in collagen vascular diseases, hypertension, diabetes mellitus, metabolic syndrome X, psoriasis, Alzheimer's disease, schizophrenia, depression, CHD, atherosclerosis, and cancer [17–25]. In all these conditions, plasma and tissue levels of GLA, DGLA, AA, EPA, and DHA are significantly low compared to normal suggesting that EFA/PUFA deficiency either predisposes or initiates the onset of these diseases [5, 7, 10–12, 15–25]. EFAs/PUFAs play a significant role in such diverse conditions due to their ability to modulate cell membrane fluidity, possess second messenger action, influence angiotensin converting and HMG-CoA reductase enzymes, serve as ligands for nuclear receptors PPARs (peroxisome proliferator-activated receptors), LXR (liver X receptor), FXR (Farnesol X receptor), HNF-4α (hepatocyte nuclear factor-4α), enhance endothelial nitric oxide (eNO) generation, suppress leukocyte activation and production of pro-inflammatory cytokines IL-6 and TNF-α, prevent platelet aggregation, and regulate telomere length (reviewed in ). In addition, PUFAs form precursors to potent anti-inflammatory molecules: lipoxins, resolvins, and protectins that are essential to suppress inflammatory process and enhance healing [15, 16].
In this context, it is noteworthy that saturated fats, cholesterol, trans-fatty acids, alcohol, adrenaline, and glucocorticoids inhibit Δ6 and Δ5 desaturases; pyridoxine, zinc, nicotinic acid, and magnesium are co-factors for normal Δ6 desaturase activity; whereas insulin activates Δ6 desaturase; and diabetics, hypertensives, and those with hyperlipidemias have reduced Δ6 and Δ5 desaturase (Δ6 > Δ5) activities [15, 16]. The activity of Δ6 desaturase falls with age. Oncogenic viruses including hepatitis C virus and radiation inhibit Δ6 desaturase activity. Total fasting, protein deficiency, and a glucose-rich diet reduce, whereas fat-free diet and partial caloric restriction enhance Δ6 desaturase activity. Activity of Δ6 and Δ5 desaturases are regulated by sterol regulatory element binding protein-1 (SREBP-1) and peroxisome proliferator-activated receptor-α (PPAR-α), two reciprocal transcription factors for fatty acid metabolism, and some of their (SREBP-1 and PPAR-α) lipogenic functions are brought about by their action on PUFAs . Interference with the metabolism of EFAs by saturated fats, cholesterol and trans fats, glucose, insulin deficiency, viruses, alcohol, and ageing reduces the formation of GLA, DGLA, AA, EPA, and DHA and their beneficial metabolites prostacyclin (PGI2), PGI3, lipoxins, resolvins, and protectins that could account for the initiation and progression of atherosclerosis, persistence of inflammation, CHD and failure of the healing process [15, 16, 19, 24].
It is evident from the preceding discussion that EFAs/PUFAs are not only naturally occurring endogenous substances present in almost all tissues and essential components of all mammalian cells but also useful in the prevention and treatment of low-grade systemic inflammatory conditions: atherosclerosis, CHD, stroke, diabetes mellitus, hypertension, cancer, depression, schizophrenia, Alzheimer's disease, and collagen vascular diseases if they are present in adequate amounts in various target tissues [15–26]; and function as endogenous anti-biotic-like molecules [36, 37, 44]. EFAs/PUFAs have aspirin-like action, inhibit of HMG-CoA and ACE enzymes, and possess diuretic, anti-hypertensive, and β-blocker-like actions, which suggests that they (PUFAs) function as endogenous "polypill" and thus, prevent cardiovascular mortality and morbidity .
Dietary intake of PUFAs (especially ω-3) from infancy reduced the risk for type 1 diabetes  confirming previous animal studies that PUFAs prevent chemical-induced diabetes [22, 23]. Increasing concentrations of ω-6 DGLA and AA in breast milk reduced the risk of mother-to-child transmission of HIV  suggesting that PUFAs have anti-HIV actions [39, 40]. Since many low-grade systemic inflammatory conditions may have their origins in the perinatal period , I propose that PUFAs be given to pregnant women and lactating mothers and to children from infancy throughout life to reduce the burden of both infectious and non-infectious diseases.
This hypothesis can be tested by studying the effect of supplementation of ω-3 and ω-6 fatty acids (in different combinations and doses) in animal models of various human diseases. It is envisaged in this hypothesis that the plasma and tissue concentrations of various PUFAs and their beneficial metabolites such as PGI2, PGE1, lipoxins, resolvins, and protectins will be lower in various low-grade systemic inflammatory conditions compared to normal. This hypothesis implies that in subjects who have lower normal levels and those who are marginally deficient in PUFAs are more likely to develop HCV, HIV, malaria, and bacterial infections. If this hypothesis is true, it indicates that those who fail to produce adequate amounts of lipoxins, resolvins, and protectins are less likely to recover from these diseases in time. Since, various PUFAs can be obtained from diet or supplemented from external sources; it will be interesting to study the therapeutic benefits of various ω-3 and ω-6 fatty acids in the diseases that have been enumerated above. It is important to study which type (ω-3, ω-6 or both) of fatty acids and in what combination or ratio and which form (oral or parenteral) are most suited to suppress or give relief from various diseases. It is relevant to study whether suitable synthetic analogues of various PUFAs can be developed for their possible therapeutic use in various diseases. Since most of the low-grade systemic inflammatory conditions have their origin in the perinatal period and childhood, it is important that studies are performed wherein PUFAs are given from infancy and wherever possible to the mother during pregnancy and lactation till adult age to know whether such long (sometimes even lifelong) term supplementation is necessary to suppress or postpone the development of the disease or at least decrease the severity of the disease in the event it occurs. Since PUFAs are relatively safe even when taken for long periods of time, such intervention studies in humans are not difficult. Preliminary studies [49, 50] are already in support of such an intervention in humans.
- Lopez A, Mathers C, Ezzati M, Jamison D, Murray C: Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet. 2006, 367: 1714-1717. 10.1016/S0140-6736(06)68770-9View ArticleGoogle Scholar
- Ezzati M, Vander Hoom S, Lawes C: Rethinking the "Diseases of Affluence" paradigm: global patterns of nutritional risks in relation to economic development. PLoS Med. 2005, 2: e133- 10.1371/journal.pmed.0020133PubMed CentralView ArticlePubMedGoogle Scholar
- Lim SS, Gaziana TA, Gakidou E, Reddy KS, Farzadfar F, Lozana R, Rodgers A: Prevention of cardiovascular disease in high-risk individuals in low-income and middle-income countries: health effects and costs. Lancet. 2007, 370: 2054-2625. 10.1016/S0140-6736(07)61699-7View ArticlePubMedGoogle Scholar
- Das UN: Hypertension as a low-grade systemic inflammatory condition that has its origins in the perinatal period. J Assoc Physicians India. 2006, 54: 133-142.PubMedGoogle Scholar
- Luc G, Bard J-M, Juhan-Vague I: C-reactive protein, interleukins-6, and fibrinogen as predictors of coronary heart disease. The PRIME study. Arterioscler Thromb Vasc Biol. 2003, 23: 1255-1261. 10.1161/01.ATV.0000079512.66448.1DView ArticlePubMedGoogle Scholar
- Das UN: Is obesity an inflammatory condition?. Nutrition. 2001, 17: 953-966. 10.1016/S0899-9007(01)00672-4View ArticlePubMedGoogle Scholar
- Das UN: Aberrant expression of perilipins and 11-β-HSD-1 as molecular signatures of metabolic syndrome X in South East Asians. J Assoc Physicians India. 2006, 54: 637-649.PubMedGoogle Scholar
- Ridker PM, Buring JE, Cook NR, Rifai N: C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events. Circulation. 2003, 107: 391-397. 10.1161/01.CIR.0000055014.62083.05View ArticlePubMedGoogle Scholar
- Das UN: Is metabolic syndrome X a disorder of the brain with the initiation of low-grade systemic inflammatory events during the perinatal period?. J Nutr Biochem. 2007, 18: 701-713. 10.1016/j.jnutbio.2007.01.002View ArticlePubMedGoogle Scholar
- Das UN: Folic acid and polyunsaturated fatty acids improve cognitive function and prevent depression, dementia, and Alzheimer's disease – but how and why?. Prostaglandins Leukot Essent Fatty Acids. 2008, 78: 11-19. 10.1016/j.plefa.2007.10.006View ArticlePubMedGoogle Scholar
- Das UN: Is depression a low-grade systemic inflammatory condition?. Am J Clin Nutr. 2007, 85: 1665-1666.PubMedGoogle Scholar
- Dougan M, Dranoff G: Inciting inflammation: the RAGE about tumor promotion. J Exp Med. 2008, 205: 267-270. 10.1084/jem.20080136PubMed CentralView ArticlePubMedGoogle Scholar
- Lawrence T, Hagemann T, Balkwill F: Sex, cytokines, and cancer. Science. 2007, 317: 51-52. 10.1126/science.1146052View ArticlePubMedGoogle Scholar
- Das UN: Essential fatty acids: Biochemistry, physiology, and pathology. Biotech J. 2006, 1: 420-439. 10.1002/biot.200600012View ArticleGoogle Scholar
- Das UN: Essential fatty acids – a review. Current Pharmaceutical Biotechnology. 2006, 7: 467-482. 10.2174/138920106779116856View ArticlePubMedGoogle Scholar
- Das UN: Long-chain polyunsaturated fatty acids interact with nitric oxide, superoxide anion, and transforming growth factor-β to prevent human essential hypertension. Eur J Clin Nutr. 2004, 58: 195-203. 10.1038/sj.ejcn.1601766View ArticlePubMedGoogle Scholar
- Das UN: A Perinatal Strategy for Preventing Adult Diseases: The Role of Long-Chain Polyunsaturated Fatty Acids. 2002, Kluwer Academic Publishers, Boston.View ArticleGoogle Scholar
- Das UN: A defect in the activity of Δ6 and Δ5 desaturases may be a factor predisposing to the development of insulin resistance syndrome. Prostaglandins Leukot Essen Fatty Acids. 2005, 72: 343-350. 10.1016/j.plefa.2005.01.002. 10.1016/j.plefa.2005.01.002View ArticleGoogle Scholar
- Das UN: Essential fatty acid metabolism in patients with essential hypertension, diabetes mellitus and coronary heart disease. Prostaglandins Leukot Essen Fatty Acids. 1995, 52 (6): 387-391. 10.1016/0952-3278(95)90066-7View ArticleGoogle Scholar
- Das UN: Beneficial effect(s) of n-3 fatty acids in cardiovascular diseases: but, why and how?. Prostaglandins Leukot Essen Fatty Acids. 2000, 63 (6): 351-362. 10.1054/plef.2000.0226View ArticleGoogle Scholar
- Suresh Y, Das UN: Differential effect of saturated, monounsaturated, and polyunsaturated fatty acids on alloxan-induced diabetes mellitus. Prostaglandins Leukot Essen Fatty Acids. 2006, 74 (3): 199-213. 10.1016/j.plefa.2005.11.006View ArticleGoogle Scholar
- Das UN: A defect in the activity of Δ6 and Δ5 desaturases may be a factor in the initiation and progression of atherosclerosis. Prostaglandins Leukot Essen Fatty Acids. 2007, 76: 251-268. 10.1016/j.plefa.2007.03.001. 10.1016/j.plefa.2007.03.001View ArticleGoogle Scholar
- Das UN: Gamma-linolenic acid, arachidonic acid and eicosapentaenoic acid as potential anti-cancer drugs. Nutrition. 1990, 6: 429-434.PubMedGoogle Scholar
- Das UN: Can perinatal supplementation of long-chain polyunsaturated fatty acids prevents schizophrenia in adult life?. Med Sci Monit. 2004, 10: HY33-HY37.PubMedGoogle Scholar
- Das UN: Beneficial actions of polyunsaturated fatty acids in cardiovascular diseases: But, how and why?. Current Nutr Food Sci. 2008, 4: 2-31. 10.2174/157340108783497418. 10.2174/157340108783497418View ArticleGoogle Scholar
- Matsuzaka T, Shimano H, Yahagi N: Dual regulation of mouse Delta(5)- and Delta(6)-desaturase gene expression by SREBP-1 and PPARalpha. J Lipid Res. 2002, 43: 107-114.PubMedGoogle Scholar
- Galbraith H, Miller TB, Paton AM, Thompson JK: Antibacterial activity of long chain fatty acids and the reversal with calcium, magnesium, ergocalciferol and cholesterol. J Appl Bact. 1971, 34 (4): 803-813.View ArticleGoogle Scholar
- Kohn A, Gitelman J, Inbar M: Unsaturated free fatty acids inactivate animal enveloped viruses. Arch Virol. 1980, 66: 301-307. 10.1007/BF01320626View ArticlePubMedGoogle Scholar
- Kumaratilake LM, Robinson BS, Ferrante A, Poulos A: Antimalarial properties of n-3 and n-6 polyunsaturated fatty acids: in vitro effects on Plasmodium falciparum and in vivo effects on P. berghei. J Clin Invest. 1992, 89: 961-967. 10.1172/JCI115678PubMed CentralView ArticlePubMedGoogle Scholar
- Krugloak M, Deharo E, Shalmiev G, Sauvain M, Moretti C, Ginsburg H: Antimalarial effects of C18 fatty acids on Plasmodium falciparum in culture and on Plasmodium vinckei petteri and Plamodium yoelii nigeriensis in vivo. Exp Parasitology. 1995, 81: 97-105. 10.1006/expr.1995.1097. 10.1006/expr.1995.1097View ArticleGoogle Scholar
- Taylor DW, Levander OA, Krishna VR, Evans CB, Morris VC, Barta JR: Vitamin E-deficient diets enriched with fish oil suppress lethal Plasmodium yoelii infections in athymic and scid/bg mice. Infect Immun. 1997, 65: 197-202.PubMed CentralPubMedGoogle Scholar
- Doering TL, Raper J, Buxbaum LU, Adams SP, Gordon JI, Hart GW, Englund PT: An analog of myristic acid with selective toxicity for African Trypanosomes. Science. 1991, 252: 1851-1854. 10.1126/science.1829548View ArticlePubMedGoogle Scholar
- Giron DJ: Inhibition of viral replication in cell cultures treated with prostaglandins E1. Proc Soc Exp Biol Med. 1982, 170: 25-28.View ArticlePubMedGoogle Scholar
- Santoro MG, Benedetto A, Carruba G, Garaci E, Jaffe BM: Prostaglandin A compounds as antiviral agents. Science. 1980, 209: 1032-1034. 10.1126/science.6157190View ArticlePubMedGoogle Scholar
- Das UN: Antibiotic-like action of essential fatty acids. Canadian Med Assoc J. 1985, 132 (12): 1350-Google Scholar
- Das UN: Do unsaturated fatty acids function as endogenous anti-bacterial and anti-viral molecules?. Am J Clin Nutr. 2006, 83: 390-391.PubMedGoogle Scholar
- Giamarellos-Bourboulis EJ, Mouktaroudi M, Adamis T: n-6 polyunsaturated fatty acids enhance the activities of ceftazidime and amikacin in experimental sepsis caused by multidrug-resistant Pseudomonas aeroginosa. Antimicrob Agents Chemother. 2004, 48: 4713-4717. 10.1128/AAC.48.12.4713-4717.2004PubMed CentralView ArticlePubMedGoogle Scholar
- Das UN: Can essential fatty acid deficiency predispose to AIDS?. Canadian Med Assoc J. 1985, 132 (8): 900-902.Google Scholar
- Das UN: Essential fatty acids and acquired immunodeficiency syndrome. Med Sci Monit. 2005, 11: RA206-RA211.PubMedGoogle Scholar
- Passi S, De Luca C, Picardo M, Morrone A, Ippolito F: Blood deficiency values of polyunsaturated fatty acids of phospholipids, vitamin E and glutathione peroxidase as possible risk factors in the onset and development of acquired immunodeficiency syndrome. G Ital Dermatol Venereol. 1990, 125: 125-130.PubMedGoogle Scholar
- Begin ME, Manku MS, Horrobin DF: Plasma fatty acid levels in patients with acquired immune deficiency syndrome and in controls. Prostaglandins Leukot Essent Fatty Acids. 1989, 37: 135-137. 10.1016/0952-3278(89)90110-5View ArticlePubMedGoogle Scholar
- Bromberg Y, Pick E: Unsaturated fatty acids stimulate NADPH-dependent superoxide production by cell-free system derived from macrophages. Cell Immunol. 1984, 88: 213-221. 10.1016/0008-8749(84)90066-2View ArticlePubMedGoogle Scholar
- Leu GZ, Lin TY, Hsu JT: Anti-HCV activities of selective polyunsaturated fatty acids. Biochem Biophys Res Commun. 2004, 318: 275-280. 10.1016/j.bbrc.2004.04.019View ArticlePubMedGoogle Scholar
- Kapadia SB, Chisari FV: Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci USA. 2005, 102: 2561-2566. 10.1073/pnas.0409834102PubMed CentralView ArticlePubMedGoogle Scholar
- Huang H, Chen Y, Ye J: Inhibition of hepatitis C virus replication by peroxidation of arachidonate and restoration by vitamin E. Proc Natl Acad Sci USA. 2007, 104: 18666-18670. 10.1073/pnas.0708423104PubMed CentralView ArticlePubMedGoogle Scholar
- Das UN: From bench to the clinic: γ-linolenic acid therapy of human gliomas. Prostaglandins Leukot Essen Fatty Acids. 2004, 70 (6): 419-426.View ArticleGoogle Scholar
- Das UN: Do polyunsaturated fatty acids behave as endogenous "polypill"?. Med Hypotheses. 2008, 70: 430-434. 10.1016/j.mehy.2007.05.023View ArticlePubMedGoogle Scholar
- Norris JM, Yin X, Lamb MM: Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at risk for type 1 diabetes. JAMA. 2007, 298: 1420-1428. 10.1001/jama.298.12.1420View ArticlePubMedGoogle Scholar
- Villamor E, Koulinska IN, Furtado J: Long-chain n-6 polyunsaturated fatty acids in breast milk decrease the risk of HIV transmission through breastfeeding. Am J Clin Nutr. 2007, 86: 682-689.PubMedGoogle Scholar
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