Omega-3 metabolism

Omega-3 Fatty Acids in Inflammation and Autoimmune Diseases -2

Artemis P. Simopoulos, MD, FACN Return to main Omega-3 page

The Center for Genetics, Nutrition and Health, Washington, D.C

	Introduction

The first evidence of the important role of dietary intake of omega-3 polyunsaturated fatty acids (PUFAs) in inflammation was derived from epidemiological observations of the low incidence of autoimmune and inflammatory disorders, such as psoriasis, asthma and type-1 diabetes, as well as the complete absence of multiple sclerosis, in a population of Greenland Eskimos compared with gender- and age-matched groups living in Denmark [1]. Most of these diseases are characterized by inappropriate activation of T cells resulting on and ultimately destruction of host tissues.
In the 1980’s several independent lines of evidence suggested that changes in the natural history of hypertensive, atherosclerotic and chronic inflammatory disorders may be achieved by altering availability of eicosanoid precursors. Native Greenland Eskimos [2] and Japanese [3] have a high dietary intake of long chain omega-3 PUFA from seafood and a low incidence of myocardial infarction and chronic inflammatory or autoimmune disorders, even when compared to their Westernized ethnic counterparts. Diets containing omega-3 PUFA have also been found to reduce the severity of experimental cerebral [4] and myocardial [5] infarction, to retard autoimmune nephritis and prolong survival of NZB x NZW F1 mice [6,7] and reduce the incidence of breast tumors in rats [8].
The 1980s were a period of expansion in our knowledge about PUFAs in general and omega-3 fatty acids in particular. Today we know that omega-3 fatty acids are essential for normal growth and development and may play an important role in the prevention and treatment of coronary artery disease, hypertension, arthritis, other inflammatory and autoimmune disorders and cancer [9]. Research has been carried out in animal models, tissue cultures and human beings. The original observational studies have given way to controlled clinical trials.
In this paper, I review the anti-inflammatory aspects of omega-3 fatty acids relative to prostaglandins and cytokines and their clinical effects in inflammatory and autoimmune diseases, such as cardiovascular disease, major depression, arthritis, inflammatory bowel disease, asthma and psoriasis.

	Omega-6 and Omega-3 Fatty Acids and Prostaglandin Metabolism

Omega-6 fatty acids account for the majority of polyunsaturated fatty acids (PUFA) in the food supply. They are the predominant PUFA in all diets, especially Western diets. When diets are supplemented with omega-3 fatty acids, the latter partially replace the omega-6 fatty acids in the membranes of practically all cells (i.e., erythrocytes, platelets, endothelial cells, monocytes, lymphocytes, granulocytes, neuronal cells, fibroblasts, retinal cells, hepatic cells and neuroblastoma cells).
Competition between the omega-6 and omega-3 fatty acids occurs in prostaglandin formation. Eicosapentaenoic acid (EPA), an omega-3 fatty acid, competes with arachidonic acid (AA), an omega-6 fatty acid, for prostaglandin and leukotriene synthesis at the cyclooxygenase and lipoxygenase level(Fig. 1). When humans ingest fish or fish oil, the EPA and docosahexaenoic acid (DHA) from fish or fish oil lead to (1) a decreased production of prostaglandin E2 (PGE2) metabolites, (2) a decrease in thromboxane A2, a potent platelet aggregator and vasoconstrictor (3) a decrease in leukotriene B4 formation, an inducer of inflammation and a powerful inducer of leukocyte chemotaxis and adherence, (4) an increase in thromboxane A3, a weak platelet aggregator and a weak vasoconstrictor, (5) an increase in prostacyclin PGI3, leading to an overall increase in total prostacyclin by increasing PGI3 without a decrease in PGI2 (both PGI2 and PGI3 are active vasodilators and inhibitors of platelet aggregation) and (6) an increase in leukotriene B5, a weak inducer of inflammation and a weak chemotactic agent [10,11]. Omega-3 fatty acids modulate prostaglandin metabolism and decrease triglycerides and, in high doses, lower cholesterol and have antithrombotic and anti-inflammatory properties. These studies were extensively reviewed and reported [12–17].

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Fig. 1. Oxidative metabolism of arachidonic acid and eicosapentaenoic acid by the cyclooxygenase and 5-lipoxygenase pathways. 5-HPETE denotes 5-hydroperoxyeicosatetranoic acid and 5-HPEPE denotes 5-hydroxyeicosapentaenoic acid.

Many factors contribute to the complex course of inflammatory reactions. Microbiological, immunological and toxic agents can initiate the inflammatory response by activating a variety of humoral and cellular mediators. In the early phase of inflammation, excessive amounts of interleukins and lipid mediators are released and play a crucial role. Pro-inflammatory eicosanoids of AA metabolism are released from membrane phospholipids in the course of inflammatory activation. EPA is released to compete with AA for enzymatic metabolism inducing the production of less inflammatory and chemotactic derivatives.
A variety of substances that inhibit the COX pathway have been investigated, including non-steroidal anti-inflammatory drugs (NSAIDs) used for the treatment of inflammation, pain and fever. Although NSAIDs inhibit COX and are efficacious anti-inflammatory agents, serious adverse effects limit their use. Two forms of COX have been identified, a constitutively expressed COX-1 and a cytokine inducible COX-2. It has been suggested that NSAID toxicity is due to inhibition of COX-1, whereas therapeutic properties are derived from COX-2 inhibition at the site of inflammation [18,19]. In addition, there is evidence that COX-2 inhibition can suppress the growth of colorectal cancer [20].
A new arena for omega-3 fatty acids has emerged as adjuvants to drug treatment leading to synergism (potentiating the effects of drugs) or to decreasing their toxicity (Table 1) [21–32].

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Table 1. Conditions in which Omega-3 Fatty Acids Have Been Shown to Have Synergistic Effects with Drugs

Similarly, increasing the intake of omega-3 fatty acids while decreasing the omega-6 fatty acids in the diet has led to improvements and a decrease of non-steroidal anti-inflammatory agents in patients with rheumatoid arthritis [33,34] and asthma [35].
Dietary fish oils, rich in omega-3 PUFA, are rapidly incorporated into the membrane phospholipids of circulating human (monocyte) cells, suggesting that they are likely to have an effect on several aspects of cell function. Moderate dietary supplementation with omega-3 PUFA significantly increases their level in monocytes within two weeks [36]. The levels of EPA reached a maximum accumulation after six weeks’ supplementation and DHA reached a peak at 18 weeks [37]. EPA returned rapidly to pretreatment levels in monocytes (although plasma levels remained significantly elevated from baseline after 24 weeks of washout) whereas DHA levels declined more slowly [37].

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Received May 21, 2002. Accepted August 15, 2002.

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Omega-3 Fatty Acids in Inflammation and Autoimmune Diseases -2