Parveen Yaqoob

Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial

BACKGROUND N-3 polyunsaturated fatty acids (PUFAs) from oily fish protect against death from cardiovascular disease. We aimed to assess the hypothesis that incorporation of n-3 and n-6 PUFAs into advanced atherosclerotic plaques increases and decreases plaque stability, respectively. METHODS We did a randomised controlled trial of patients awaiting carotid endarterectomy. We randomly allocated patients control, sunflower oil (n-6), or fish-oil (n-3) capsules until surgery. Primary outcome was plaque morphology indicative of stability or instability, and outcome measures were concentrations of EPA, DHA, and linoleic acid in carotid plaques; plaque morphology; and presence of macrophages in plaques. Analysis was per protocol. FINDINGS 188 patients were enrolled and randomised; 18 withdrew and eight were excluded. Duration of oil treatment was 7-189 days (median 42) and did not differ between groups. The proportions of EPA and DHA were higher in carotid plaque fractions in patients receiving fish oil compared with those receiving control (absolute difference 0.5 [95% CI 0.3-0.7], 0.4 [0.1-0.6], and 0.2 [0.1-0.4] g/100 g total fatty acids for EPA; and 0.3 [0.0-0.8], 0.4 [0.1-0.7], and 0.3 [0.1-0.6] g/100 g total fatty acids for DHA; in plaque phospholipids, cholesteryl esters, and triacylglycerols, respectively). Sunflower oil had little effect on the fatty acid composition of lipid fractions. Fewer plaques from patients being treated with fish oil had thin fibrous caps and signs of inflammation and more plaques had thick fibrous caps and no signs of inflammation, compared with plaques in patients in the control and sunflower oil groups (odds ratio 0.52 [95% CI 0.24-0.89] and 1.19 [1.02-1.57] vs control; 0.49 [0.23-0.90] and 1.16 [1.01-1.53] vs sunflower oil). The number of macrophages in plaques from patients receiving fish oil was lower than in the other two groups. Carotid plaque morphology and infiltration by macrophages did not differ between control and sunflower oil groups. INTERPRETATION Atherosclerotic plaques readily incorporate n-3 PUFAs from fish-oil supplementation, inducing changes that can enhance stability of atherosclerotic plaques. By contrast, increased consumption of n-6 PUFAs does not affect carotid plaque fatty-acid composition or stability over the time course studied here. Stability of plaques could explain reductions in non-fatal and fatal cardiovascular events associated with increased n-3 PUFA intake.

Fatty acids and lymphocyte functions

The immune system acts to protect the host against pathogenic invaders. However, components of the immune system can become dysregulated such that their activities are directed against host tissues, so causing damage. Lymphocytes are involved in both the beneficial and detrimental effects of the immune system. Both the level of fat and the types of fatty acid present in the diet can affect lymphocyte functions. The fatty acid composition of lymphocytes, and other immune cells, is altered according to the fatty acid composition of the diet and this alters the capacity of those cells to produce eicosanoids, such as prostaglandin E2, which are involved in immunoregulation. A high fat diet can impair lymphocyte function. Cell culture and animal feeding studies indicate that oleic, linoleic, conjugated linoleic, gamma-linolenic, dihomo-gamma-linolenic, arachidonic, alpha-linolenic, eicosapentaenoic and docosahexaenoic acids can all influence lymphocyte proliferation, the production of cytokines by lymphocytes, and natural killer cell activity. High intakes of some of these fatty acids are necessary to induce these effects. Among these fatty acids the long chain n-3 fatty acids, especially eicosapentaenoic acid, appear to be the most potent when included in the human diet. Although not all studies agree, it appears that fish oil, which contains eicosapentaenoic acid, down regulates the T-helper 1-type response which is associated with chronic inflammatory disease. There is evidence for beneficial effects of fish oil in such diseases; this evidence is strongest for rheumatoid arthritis. Since n-3 fatty acids also antagonise the production of inflammatory eicosanoid mediators from arachidonic acid, there is potential for benefit in asthma and related diseases. Recent evidence indicates that fish oil may be of benefit in some asthmatics but not others.

Encapsulated fish oil enriched in α‐tocopherol alters plasma phospholipid and mononuclear cell fatty acid compositions but not mononuclear cell functions

Several studies have reported that dietary fish oil (FO) supplementation alters cytokine production and other functional activities of peripheral blood mononuclear cells (PBMC). However, few of these studies have been placebo controlled and few have related the functional changes to alterations in PBMC fatty acid composition

Omega-3 polyunsaturated fatty acids and human health outcomes

Current intakes of very long chain ω‐3 fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are low in most individuals living in Western countries. A good natural source of these fatty acids is seafood, especially oily fish. Fish oil capsules contain these fatty acids too. Very long chain ω‐3 fatty acids are readily incorporated from capsules into transport, functional, and storage pools. This incorporation is dose‐dependent and follows a kinetic pattern that is characteristic for each pool. At sufficient levels of incorporation, EPA and DHA influence the physical nature of cell membranes and membrane protein‐mediated responses, eicosanoid generation, cell signaling and gene expression in many different cell types. Through these mechanisms, EPA and DHA influence cell and tissue physiology, and the way cells and tissues respond to external signals. In most cases, the effects seen are compatible with improvements in disease biomarker profiles or in health‐related outcomes. As a result, very long chain ω‐3 fatty acids play a role in achieving optimal health and in protection against disease. Long chain ω‐3 fatty acids protect against cardiovascular morbidity and mortality, and might be beneficial in rheumatoid arthritis, inflammatory bowel diseases, childhood learning, and behavior, and adult psychiatric and neurodegenerative illnesses. DHA has an important structural role in the eye and brain, and its supply early in life is known to be of vital importance. On the basis of the recognized health improvements brought about by long chain ω‐3 fatty acids, recommendations have been made to increase their intake.

Dietary fatty acids influence the production of Th1- but not Th2-type cytokines

C57Bl6 mice were fed for 6 weeks on a low‐fat diet or on high‐fat diets containing coconut oil (rich in saturated fatty acids), safflower oil [rich in n‐6 polyunsaturated fatty acids (PUFAs)], or fish oil (rich in n‐3 PUFAs) as the main fat sources. The fatty acid composition of the spleen lymphocytes was influenced by that of the diet fed. Thymidine incorporation into concanavalin A‐stimulated spleen lymphocytes and interleukin (IL)‐2 production were highest after feeding the coconut oil diet. Interferon (IFN)‐γ production was decreased by safflower oil or fish oil feeding. IL‐4 production was not significantly affected by diet, although production was lowest by lymphocytes from fish oil‐fed mice. The ratio of production of Th1‐ to Th2‐type cytokines (determined as the IFN‐γ/IL‐4 ratio) was lower for lymphocytes from mice fed the safflower oil or fish oil diets. After 4 h of culture, IL‐2 mRNA levels were higher in cells from mice fed coconut oil, and IFN‐γ mRNA levels were higher in cells from mice fed coconut oil or safflower oil. After 8 h of culture, IL‐2, IFN‐γ, and IL‐4 mRNA levels were lowest in cells from mice fed fish oil. The ratio of the relative levels of IFN‐γ mRNA to IL‐4 mRNA was highest in cells from mice fed coconut oil and was lowest in cells of mice fed fish oil. The influence of individual fatty acids on IL‐2 production by murine spleen lymphocytes was examined in vitro. Although all fatty acids decreased IL‐2 production in a concentration‐dependent manner, saturated fatty acids were the least potent and n‐3 PUFAs the most potent inhibitors, withn‐6 PUFAs falling in between in terms of potency. It is concluded that saturated fatty acids have minimal effects on cytokine production. In contrast, PUFAs act to inhibit production of Th1‐type cytokines with little effect on Th2‐type cytokines; n‐3 PUFAs are particularly potent. The effects of fatty acids on cytokine production appear to be exerted at the level of gene expression.

Glutamine and the immune system.

SummaryGlutamine is utilised at a high rate by cells of the immune system in culture and is required to support optimal lymphocyte proliferation and production of cytokines by lymphocytes and macrophages. Macrophage-mediated phagocytosis is influenced by glutamine availability. Hydrolysable glutamine dipeptides can substitute for glutamine to support in vitro lymphocyte and macrophage functions. In man plasma and skeletal muscle glutamine levels are lowered by sepsis, injury, burns, surgery and endurance exercise and in the overtrained athlete. The lowered plasma glutamine concentrations are most likely the result of demand for glutaminne (by the liver, kidney, gut and immune system) exceeding the supply (from the diet and from muscle). It has been suggested that the lowered plasma glutamine concentration contributes, at least in part, to the immunosuppression which accompanies such situations. Animal studies have shown that inclusion of glutamine in the diet increases survival to a bacterial challenge. Glutamine or its precursors has been provided, usually by the parenteral route, to patients following surgery, radiation treatment or bone marrow transplantation or suffering from injury. In most cases the intention was not to stimulate the immune system but rather to maintain nitrogen balance, muscle mass and/or gut integrity. Nevertheless, the maintenance of plasma glutamine concentrations in such a group of patients very much at risk of immunosuppression has the added benefit of maintaining immune function. Indeed, the provision of glutamine to patients following bone marrow transplantation resulted in a lower level of infection and a shorter stay in hospital than for patients receiving glutamine-free parenteral nutrition.

Understanding omega-3 polyunsaturated fatty acids

Abstract Current intakes of very long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are low in most individuals living in Western countries. A good natural source of these fatty acids is seafood, especially oily fish. Fish oil capsules contain these fatty acids also. Very long-chain omega-3 fatty acids are readily incorporated from capsules into transport (blood lipids), functional (cell and tissue), and storage (adipose) pools. This incorporation is dose-dependent and follows a kinetic pattern that is characteristic for each pool. At sufficient levels of incorporation, EPA and DHA influence the physical nature of cell membranes and membrane protein-mediated responses, lipid-mediator generation, cell signaling, and gene expression in many different cell types. Through these mechanisms, EPA and DHA influence cell and tissue physiology and the way cells and tissues respond to external signals. In most cases the effects seen are compatible with improvements in disease biomarker profiles or health-related outcomes. As a result, very long-chain omega-3 fatty acids play a role in achieving optimal health and in protection against disease. Long-chain omega-3 fatty acids not only protect against cardiovascular morbidity but also against mortality. In some conditions, for example rheumatoid arthritis, they may be beneficial as therapeutic agents. On the basis of the recognized health improvements brought about by long-chain omega-3 fatty acids, recommendations have been made to increase their intake. The plant omega-3 fatty acid, alpha-linolenic acid (ALA), can be converted to EPA, but conversion to DHA appears to be poor in humans. Effects of ALA on human health-related outcomes appear to be due to conversion to EPA, and since this is limited, moderately increased consumption of ALA may be of little benefit in improving health outcomes compared with increased intake of preformed EPA + DHA.

Inhibition of natural killer cell activity by dietary lipids

Natural killer (NK) cells are a subset of cytotoxic lymphocytes found mainly in blood and the spleen. NK cells play a role in natural immunity to microbes, viruses and tumor cells and are involved in the rejection of grafts. The present study investigated the effects of diets containing oils rich in saturated fatty acids, mono-unsaturated fatty acids, n-6-poly-unsaturated fatty acids (PUFA) or n-3-PUFA on the NK cell activity and on the lymphokine-activated killer (LAK) cell activity of rat spleen lymphocytes. Weanling rats were fed for 10 weeks on a low-fat (LF) diet (approximately 2% fat by weight) or on 1 of 5 high-fat (HF) diets, which contained 20% (by weight) hydrogenated coconut oil (HCO), olive oil (OO), safflower oil (SO), evening primrose oil (EPO) or menhaden (fish) oil (MO). Each of the HF diets suppressed the NK activity of freshly prepared spleen lymphocytes compared with the LF diet; cells from the MO-fed rats exhibited the lowest NK activity. Culture with IFN alpha for 3 h increased the NK activity of spleen lymphocytes from all animals, except those fed the OO diet; the increase in NK activity varied from 20% (LF) to 50% (MO). Although feeding the OO, EPO or MO diets resulted in lower IFN alpha-stimulated NK activity than that obtained by feeding the LF diet, the only consistent significant difference was the lower activity of the cells from the OO-fed rats compared with those from the LF-fed rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Fatty acids and the immune system: from basic science to clinical applications

Over the last 25 years, the effects of fatty acids on the immune system have been characterized using in vitro, animal and human studies. Advances in fatty acid biochemistry and molecular techniques have recently suggested new mechanisms by which fatty acids could potentially modify immune responses, including modification of the organization of cellular lipids and interaction with nuclear receptors. Possibilities for the clinical applications of n-3 PUFA are now developing. The present review focuses on the hypothesis that the anti-inflammatory properties of n-3 PUFA in the arterial wall may contribute to the protective effects of n-3 PUFA in CVD, as suggested by epidemiological and secondary prevention studies. Studies are just beginning to show that dietary n-3 PUFA can be incorporated into plaque lipid in human subjects, where they may influence the morphology and stability of the atherosclerotic lesion.

Nutritional and health aspects of olive oil

This review describes the types of lipids in human diets and their possible implications for health and disease. The high oleate and significant linoleate contents of olive oil are important for nutrition; moreover, when olive oil is used for deep-fat frying, as in a typ- ical “Mediterranean Diet”, then many of its desirable properties are retained and there is much less deterioration than for some other cooking oils. The health-promoting ef- fects of olive oil have been cited anecdotally for many years. However, as highlighted in this review, the scientific basis for these effects is still unclear. In this review, partic- ular attention is paid to obesity, cardiovascular disease, cancer and inflammatory dis- eases. There is good evidence that olive oil is protective in cardiovascular diseases. Its mechanism of action may involve effects on blood lipids, but other mechanisms, in- cluding effects on immune function, endothelial function and the coagulation pathways remain possible and are discussed. The effects of olive oil in obesity and cancer are less clear. Finally, many questions still remain about the potential health effects of the many non-lipid components of olive oil.