Current Organic Chemistry - Volume 4, Issue 11, 2000

Dietary n-3 fatty acids and calorie restriction are well known immunomodulatory nutrients. Recent data from our laboratory has shown that combining n-3 fatty acids and calorie restriction is more potent at delaying autoimmune disease in mice than either dietary regimen alone. Interestingly, autoimmune disease has some unique effects on lymphocyte subsets and Th-1 (inter-leukin-2, interferon-g) and Th-2 (interleukin-10 and -5) cytokine and immunoglobulin (IgA and IgE) production when comparing the peripheral blood with the spleen, mesenteric lymph nodes and salivary glands. However, regardless of the variable changes that occur due to n-6 and n-3 fatty acids, the combination of dietary n-3 fatty acids and/or calorie restriction prevents immune cell dysregulation. Extensive studies conducted in spleen T-cells have shown that diet, in the absence of pharmacologic or genetic manipulation, has a dramatic impact on preventing alterations in apoptosis, memory cell populations, and nuclear factor kappa B activation associated with autoimmune disease. The results discussed here also show striking similarities to aging in healthy mice like reduced interleukin-2 production and increased memory T-lymphocytes suggesting a clear link between normal aging and the early development of autoimmune disease. Future dietary studies examining several different immune compartments simultaneously are likely to yield exciting new data on the impact of diet and drug therapy on autoimmune disorders in various target tissues such as kidney and salivary glands.

The consumption of fish and omega-3 fatty acids has been associated with reduced morbidity and mortality from coronary heart disease. The precise mechanisms by which fatty acids modulate atherosclerotic vascular disease remain to be defined. Experimental evidence suggests that fatty acids alter the function of the vascular endothelium, a metabolically active tissue that integrates signals between the circulation and the vascular wall. This review focuses on the effects of fatty acids on vascular endothelial nitric oxide production. Endothelial-derived nitric oxide regulates several vascular wall events that participate in the evolution of vascular disease. Impairment of endothelial nitric oxide production has been demonstrated in a variety of conditions such as smoking, diabetes, and hypertension that are risk factors for atherosclerosis. Evidence is reviewed that supports the postulate that both qualitative and quantitative alterations in circulating fatty acid species modulate vascular endothelial nitric oxide production. Although the mechanisms by which fatty acids alter vascular nitric oxide production remain obscure, fatty acid-mediated alterations in endothelial gene expression present a promising area for future investigation.

The data presented in this review describe consistent and reproducible beneficial effects of n-3 fatty acids on bone metabolism and bone/joint disease. Polyunsaturated fatty acids (PUFA) modulate eicosanoid biosynthesis in numerous tissues and cell types, alter signal transduction, and influence gene expression. The effect of n-6 and n-3 polyunsaturated fatty acids on cardiovascular disease, certain cancer and bone/joint health is related to the newer discoveries of how dietary PUFA impact health. Since the prostanoid PGE2 plays an important role in bone metabolism and inflammatory process, we speculate that by modulating the dietary ratio of n-6/n-3 fatty acids, bone growth could be optimized during bone modeling and bone mass better maintained during bone remodeling. Future research on n-3 fatty acids should focus on two aspects of bone. The first, to further elucidate the effects of n-3 fatty acids on biochemical and molecular factors that are involved in bone modeling, remodeling, and disease processes. The second, to evaluate the pharmaceutical interactions and applications of these nutraceutical fatty acids in maintaining bone mineral status and controlling inflammatory bone/joint diseases.

Epidemiological studies of Greenland Eskimos and Japanese have suggested that eating fish oil and marine animals can prevent heart disease. The beneficial effects of fish oils are attributed to their omega 3-fatty acid (O3Fa) content, particularly, eicosapentaenoic acid (EPA, 20 5n-3) and docosahexaenoic acid (DHA, 22 6n-3). DHA and EPA in the diet influence the fatty acid composition of plasma membrane phospholipids in cardiac tissues, which may affect cardiac cell functions. However, very little is known about the cellular and molecular mechanisms that mediate O3FA-induced cardio-protective effects. This review describes the potential cellular targets that can be modulated by O3Fas to regulate cardiac-related illnesses, particularly, cardiomyocyte hypertrophy. Among various biochemical derangements, the increase in intracellular Ca2+ ((Ca2+)i) allows the development of cardiac hypertrophy. Elevation of (Ca2+)i acts as a central intracellular signaling system by which hormones and growth factors regulate many different processes, such as secretion, metabolism, cell growth, differentiation, and cell contractility. Recent studies clearly suggest that O3Fas have profound effects on reducing (Ca2+)i levels by regulating both influx of Ca2+ through Ca2+ channels and mobilization of Ca2+ from intracellular stores. These fatty acids modulate Ca2+ current through the L-type calcium channels, and the effects occur within minutes of adding EPA or DHA to the medium. O3FAs can also regulate calcium mobilization from intracellular stores by affecting phosphatidylinositol cycle, phospholipase C activities, and inositol 1, 4, 5 trisphosphate generation. The effect of O3FAs on reducing the (Ca2+)i levels could be one of the mechanisms for preventing cardiac hypertrophy. In addition to affecting [Ca2+]i levels, these fatty acids can also affect other signaling pathways, including alterations in receptor affinity and density, activities of adenylate and guanylate cyclase, and cyclic nucleotide phosphodiesterase activities. There is no direct evidence that O3Fas affect src, ras, and MAP kinase signal transduction pathways in cardiac tissues, but in other cellular systems these pathways can be modulated by O3FAs. It therefore appears that a blockade of src, ras, and MAP kinase pathways, which is known to be involved in the development of cardiac hypertrophy, could be an effective target for O3FAs. Another important process in the development of cardiac hypertrophy is the activation of protein kinase C (PKC) isoenzymes. PKC activation leads to stimulation of specific pathways that mediate protein synthesis in cardiomyocytes. There is clear evidence that O3Fas affect the translocation and activation of PKC in cardiac tissues through multiple mechanisms. The modulation of PKC activities therefore could be a potent target in regulating cardiac hypertrophy and other cardiac-related abnormalities. In conclusion, these recent studies suggest that O3FAs could prevent the development of hormonal-induced cardiac hypertrophy by acting on multiple cellular signaling pathways

It is now well accepted that colon cancer evolves from a multi-step process and is a disease strongly influenced by environmental factors, with diet being one of the most important modifying agents. Among dietary factors, there is cogent evidence indicating a protective effect of fish oil feeding with respect to colonic tumor development. We have recently demonstrated that the balance between colonic epithelial cell proliferation and programmed cell death (apoptosis) can be favorably modulated by feeding fish oil, containing n-3 polyunsaturated fatty acids, specifically, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). We propose that the suppression of colonic tumor development by dietary n-3 polyunsaturated fatty acids may be due to an effect on the subcellular localization of oncogenic p21 ras. The potential for fish oil feeding to antagonize ras-dependent signal transduction is significant because the acquisition of chronically activated ras via mutation or overexpression is a relatively early step in colorectal cancer development.

Docosahexaenoic acid (DHA, 22 6Delta4,7,10,13,16,19) is the longest chain and most unsaturated fatty acid commonly found in biological systems (1). It represents the extreme example of the important class of fatty acids known as omega-3s. Primarily through dietary studies, this fatty acid has been linked to an enormous variety of human afflictions including cancer (2, 3), heart disease (4), rheumatoid arthritis (5), lupus (6), alcoholism (7), blindness (8), respiratory diseases (9), peroxisomal disorders (10), cystic fibrosis (11), schizophrenia (12), depression (13), malaria (14), multiple sclerosis (15) and even migrane headaches. In order for one simple molecule to affect so many seemingly unrelated processes it must function at a fundamental level, common to most cells. It has been suggested that this level is in controlling membrane structure and function (16). Due to its extreme chain length and unsaturation it should be easier to demonstrate a unique role for DHA in membrane structure/function than it will be for other shorter, less unsaturated fatty acids commonly found in membranes. Reviewed here is the possible involvement of DHA in membrane lipid domains.

Omega-3 fatty acids are associated with a variety of health benefits from normal neurologic development and vision, to heart disease, arthritis and cancer. The Omega3 fatty acid docosahexaenoic acid in particular accumulates in biological membranes and there may serve either structural or substrate functions. Proteins resident in or associated with membranes are likely to be influenced by changes in their lipid environment. The mechanisms through which Omega3 fatty acids exert their influence over proteins are not always clear, and may include direct interactions that induce conformational change, formation of membrane lipid microdomains of unique composition; modulation of eicosanoid production; participation in oxidation; and alteration of gene expression. Much of the complexity of this area stems from the often divergent effects that Omega3 fatty acids have on different cell types in different states of activation. Here I present a sampling of proteins involved in various functions including adhesion, immunologic recognition, and signal transduction; the emphasis is on cells and processes of the immune system. Included are effects of free fatty acids and of fatty acyl chains esterified into phospholipids, and phenomena that appear unique to one or more Omega3 fatty acids or that are common to several different fatty acid classes. Understanding basic mechanisms of Omega3 fatty acid action, for example, on structure and function of membrane proteins will assist us in using these dietary components more effectively for human health.