Simopoulos A. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother, 2002; 56(8): 365-379

Several sources of information suggest that human beings evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFA) of approximately 1 whereas in Western diets the ratio is 15/1-16.7/1.

Western diets are deficient in omega-3 fatty acids, and have excessive amounts of omega-6 fatty acids compared with the diet on which human beings evolved and their genetic patterns were established.

Excessive amounts of omega-6 polyunsaturated fatty acids (PUFA) and a very high omega-6/omega-3 ratio, as is found in today's Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a low omega-6/omega-3 ratio) exert suppressive effects.

In the secondary prevention of cardiovascular disease, a ratio of 4/1 was associated with a 70% decrease in total mortality. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect.

The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk.

A ratio of 2-3/1 suppressed inflammation in patients with rheumatoid arthritis, and a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences.

These studies indicate that the optimal ratio may vary with the disease under consideration. This is consistent with the fact that chronic diseases are multigenic and multifactorial.

Therefore, it is quite possible that the therapeutic dose of omega-3 fatty acids will depend on the degree of severity of disease resulting from the genetic predisposition.

A lower ratio of omega-6/omega-3 fatty acids is more desirable in reducing the risk of many of the chronic diseases of high prevalence in Western societies, as well as in the developing countries, that are being exported to the rest of the world.

PMID: 12442909

Mori T, Beilin L. Omega-3 fatty acids and inflammation. Curr Atheroscler Rep 2004; 6(6):461-467

Dietary omega-3 (n-3) fatty acids have a variety of anti-inflammatory and immune-modulating effects that may be of relevance to atherosclerosis and its clinical manifestations of myocardial infarction, sudden death, and stroke.

The n-3 fatty acids that appear to be most potent in this respect are the long-chain polyunsaturates derived from marine oils, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and this review is restricted to these substances.

A variety of biologic effects of EPA and DHA have been demonstrated from feeding studies with fish or fish oil supplements in humans and animals. These include effects on triglycerides, high-density lipoprotein cholesterol, platelet function, endothelial and vascular function, blood pressure, cardiac excitability, measures of oxidative stress, pro- and anti-inflammatory cytokines, and immune function.

Epidemiologic studies provide evidence for a beneficial effect of n-3 fatty acids on manifestations of coronary heart disease and ischemic stroke, whereas randomized, controlled, clinical feeding trials support this, particularly with respect to sudden cardiac death in patients with established disease.

Clinically important anti-inflammatory effects in man are further suggested by trials demonstrating benefits of n-3 fatty acids in rheumatoid arthritis, psoriasis, asthma, and inflammatory bowel disorders.

Given the evidence relating progression of atherosclerosis to chronic inflammation, the n-3 fatty acids may play an important role via modulation of the inflammatory processes.

Simopoulos A. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 2002;21(6):495-505

Abstract: Among the fatty acids, it is the omega-3 polyunsaturated fatty acids (PUFA) which possess the most potent immunomodulatory activities, and among the omega-3 PUFA, those from fish oileicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are more biologically potent than alpha-linolenic acid (ALA).

Some of the effects of omega-3 PUFA are brought about by modulation of the amount and types of eicosanoids made, and other effects are elicited by eicosanoid-independent mechanisms, including actions upon intracellular signaling pathways, transcription factor activity and gene expression.

Animal experiments and clinical intervention studies indicate that omega-3 fatty acids have anti-inflammatory properties and, therefore, might be useful in the management of inflammatory and autoimmune diseases. Coronary heart disease, major depression, aging and cancer are characterized by an increased level of interleukin 1 (IL-1), a proinflammatory cytokine. Similarly, arthritis, Crohns disease, ulcerative colitis and lupus erythematosis are autoimmune diseases characterized by a high level of IL-1 and the proinflammatory leukotriene LTB4 produced by omega-6 fatty acids.

There have been a number of clinical trials assessing the benefits of dietary supplementation with fish oils in several inflammatory and autoimmune diseases in humans, including rheumatoid arthritis, Crohns disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis and migraine headaches.

Many of the placebo-controlled trials of fish oil in chronic inflammatory diseases reveal significant benefit, including decreased disease activity and a lowered use of anti-inflammatory drugs.

Barham JB, Edens MB, et al. Addition of Eicosapentaenoic Acid to Gamma-Linolenic Acid?Supplemented Diets Prevents Serum Arachidonic Acid Accumulation in Humans. J of Nutrition, 2000;130:1925-1931

Previous studies reveal that supplementation of human diets with gamma-linolenic acid (GLA) reduces the generation of lipid mediators of inflammation and attenuates clinical symptoms of chronic inflammatory disorders such as rheumatoid arthritis.
However, we have shown that supplementation with this same fatty acid also causes a marked increase in serum arachidonate (AA) levels, a potentially harmful side effect.

The objective of this study was to design a supplementation strategy that maintained the capacity of GLA to reduce lipid mediators without causing elevations in serum AA levels.

Initial in vitro studies utilizing HEP-G2 liver cells revealed that addition of eicosapentaenoic acid (EPA) blocked delta-5-desaturase activity, the terminal enzymatic step in AA synthesis.

To test the in vivo effects of a GLA and EPA combination in humans, adult volunteers consuming controlled diets supplemented these diets with 3.0 g/d of GLA and EPA.
This supplementation strategy significantly increased serum levels of EPA, but did not increase AA levels.

EPA and the elongation product of GLA, dihomo-gamma-linolenic acid (DGLA) levels in neutrophil glycerolipids increased significantly during the 3-wk supplementation period.

Neutrophils isolated from volunteers fed diets supplemented with GLA and EPA released similar quantities of AA, but synthesized significantly lower quantities of leukotrienes compared with their neutrophils before supplementation.

This study revealed that a GLA and EPA supplement combination may be utilized to reduce the synthesis of proinflammatory AA metabolites, and importantly, not induce potentially harmful increases in serum AA levels.

Johnson MM, Swan DD, Surette ME, et al. Dietary Supplementation with gamma-Linolenic Acid Alters Fatty Acid Content and Eicosanoid Production in Healthy Humans. J of Nut.,1997;127(8):1435-1444.

To understand the in vivo metabolism of dietary gamma-linolenic acid (GLA), we supplemented the diets of 29 volunteers with GLA in doses of 1.5-6.0 g/d.

Twenty-four subjects ate controlled eucaloric diets consisting of 25% fat; the remaining subjects maintained their typical Western diets. GLA and dihomo-gamma-linolenic acid (DGLA) increased in serum lipids of subjects supplemented with 3.0 and 6.0 g/d; serum arachidonic acid increased in all subjects.

GLA supplementation with 3.0 and 6.0 g/d also resulted in an enrichment of DGLA in neutrophil phospholipids but no change in GLA or AA levels.

Before supplementation, DGLA was associated primarily with phosphatidylethanolamine (PE) of neutrophil glycerolipids, and DGLA increased significantly in PE and neutral lipids after GLA supplementation. Extending the supplementation to 12 wk did not consistently change the magnitude of increase in either serum or neutrophil lipids in subjects receiving 3.0 g/d.

After GLA supplementation, A23187-stimulated neutrophils released significantly more DGLA, but AA release did not change. Neutrophils obtained from subjects after 3 wk of supplementation with 3.0 g/d GLA synthesized less leukotriene B4 (P < 0.05) and platelet-activating factor.

Together, these data reveal that DGLA, the elongase product of GLA, but not AA accumulates in neutrophil glycerolipids after GLA supplementation.

The increase in DGLA relative to AA within inflammatory cells such as the neutrophil may attenuate the biosynthesis of AA metabolites and may represent a mechanism by which dietary GLA exerts an anti-inflammatory effect.

Nassar BA, Huang YS, Manku MS et al. The influence of dietary manipulation with n-3 and n-6 fatty acids on liver and plasma phospholipid fatty acids in rats. Lipids,1986;21(10):652-656.

The interrelations between linoleic acid (LA) metabolites and fish oil fatty acids were studied.

Sprague-Dawley rats (200-220 g) were fed a fat-free semisynthetic diet supplemented with 10% (by weight) of different combinations of evening primrose oil (EPO), a rich source of LA and gamma-linolenic acid, and polepa (POL), a marine oil rich in eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids.

The combinations of supplement were as follows: 9% EPO-1% POL, 8% EPO-2% POL, 7% EPO-3% POL, 6% EPO-4% POL and 5% EPO-5% POL. After two weeks on the respective diets, the animals were killed, and the fatty acid compositions of liver and plasma phospholipids were examined.

The results showed that animals fed higher proportions of POL consistently contained higher levels of dihomo-gamma-linolenic acid (DGLA) (p less than 0.05), a metabolite of LA and GLA, and lower levels of arachidonic acid (AA) (p less than 0.01), a metabolite of DGLA through delta-5-desaturation.

Thus, an inverse relationship between AA/DGLA ratio and EPA levels was found to exist (r = -0.765 in plasma and -0.792 in liver). However, there was no such relationship between AA/DGLA ratio and DHA levels.

This result suggested that EPA but not DHA in fish oil exerts an inhibitory effect on the conversion of DGLA to AA.

News-Medical.Net

Omega-6 fatty acids promote the growth of prostate tumor cells in the laboratory

A study conducted at the San Francisco VA Medical Center (SFVAMC) has demonstrated that omega-6 fatty acids such as the fat found in corn oil promote the growth of prostate tumor cells in the laboratory.

The study also identifies a potential new molecular target for anti-tumor drugs: an enzyme known as cPLA2, which plays a key role in the chain leading from omega-6 fatty acids to prostate tumor cell growth.

The study was led by Millie Hughes-Fulford, PhD, director of the Laboratory of Cell Growth at SFVAMC and scientific advisor to the U.S. Undersecretary of Health for the Department of Veterans Affairs. It is being published in the September 2005 issue of Carcinogenesis.

Working with human prostate cancer cells in tissue culture, Hughes-Fulford and her fellow researchers identified for the first time a direct chain of causation: When introduced into prostate tumor cells in culture, omega-6 fatty acid causes the production of cPLA2, which then causes the production of the enzyme COX2. In turn, COX2 stimulates the release of PGE2, a hormone-like molecule that promotes cell growth.

"What's important about this is that omega-6 fatty acids are found in corn oil and most of the oils used in bakery goods," says Hughes-Fulford, who is also an adjunct professor of medicine at the University of California, San Francisco (UCSF).

"Which means that if you're eating a diet high in omega-6 fatty acids, it's possible that you're turning on this cancer cascade, which has been shown to be a common denominator in the growth of prostate, colorectal, and some breast cancers."

The study points out that 60 years ago in the United States, the dietary ratio of omega-6 to omega-3, a beneficial fatty acid, was 1 to 2. Today, the ratio is 25 to 1. Over that same 60 years, the incidence of prostate cancer in the U.S. has increased steadily.

Hughes-Fulford also found that flurbiprofen, a non-steroidal anti-inflammatory drug commonly prescribed for arthritis, blocked the production of cPLA2 and broke the chain leading to cell growth. This means, she says, that new drugs might be developed that could specifically target cPLA2 and prevent COX2 from being released.

"COX2 has been implicated in the growth of many types of tumors," she notes. "So if you can find a way to block that cascade in the tumor, starting with cPLA2, you might have a new way of modifying or slowing tumor growth."

Hughes-Fulford points out that cPLA2 inhibitors would avoid the problems inherent in the class of drugs known as COX2 inhibitors. These drugs have been shown to be effective against tumor growth as well as in treating the pain associated with inflammatory conditions such as arthritis, but have been implicated in increased risk of cardiovascular problems in people who take them regularly. "COX2 inhibitors also inhibit prostacyclins, which are enzymes that are beneficial to the heart, and cPLA2 inhibitors would not affect those," she explains.

In future research, Hughes-Fulford will be looking at the overall effect of different types of fatty acids on different tumor types in cell lines as well as human biopsies.

She plans a study that will correlate type of fatty acid with tumor stage and grade in order to obtain a clearer picture of specific effects of different fats on tumor progression.

Co-authors of the study were Raymond R. Tjandrawinata, PhD, of UCSF, Chai-Fei Li, BA, of SFVAMC, and Sina Sayyah, BA, of SFVAMC and UCSF.

Source: http://www.news-medical.net/?id=12176

Bagga D, Wang L, Farias-Eisner R, et al. Differential effects of prostaglandin derived from -6 and -3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion. PNAS, 2003; 10(4):1751-1756.

Omega-6 (-6) polyunsaturated fatty acids (PUFA), abundant in the Western diet, are precursors for a number of key mediators of inflammation including the 2-series of prostaglandins (PG).

PGE2, a cyclooxygenase (COX) metabolite of arachidonic acid, an omega-6 PUFA, is a potent mediator of inflammation and cell proliferation. Dietary supplements rich in omega-3 PUFA reduce the concentrations of 2-series PG and increase the synthesis of 3-series PG (e.g., PGE3), which are believed to be less inflammatory. However, studies on cellular consequences of increases in 3-series PG in comparison to 2-series PG have not been reported.

In this study, we compared the effects of PGE2 and PGE3 on (i) cell proliferation in NIH 3T3 fibroblasts, (ii) expression and transcriptional regulation of the COX-2 gene in NIH 3T3 fibroblasts, and (iii) the production of an inflammatory cytokine, IL-6, in RAW 264.7 macrophages.

PGE3, unlike PGE2, is not mitogenic to NIH 3T3 fibroblasts. PGE2 and PGE3 both induce COX-2 mRNA via similar signaling mechanisms; however, compared with PGE2, PGE3 is significantly less efficient in inducing COX-2 gene expression.

Furthermore, although both PGE2 and PGE3 induce IL-6 synthesis in RAW 264.7 macrophages, PGE3 is substantially less efficient compared with PGE2.

We further show that increasing the omega-3 content of membrane phospholipid results in a decrease in mitogen-induced PGE2 synthesis. Taken together, our data suggest that successful replacement of omega-6 PUFA with omega-3 PUFA in cell membranes can result in a decreased cellular response to mitogenic and inflammatory stimuli.