Showing papers by "Philip C. Calder published in 2007"

Immunomodulation by omega-3 fatty acids.

Abstract: The immune system, including its inflammatory components, is fundamental to host defense against pathogenic invaders. It is a complex system involving interactions amongst many different cell types dispersed throughout the body. Central to its actions are phagocytosis, processing of antigens derived from intracellular and extracellular pathogens, activation of T cells with proliferation and production of cytokines that elicit effector cell functions such as antibody production and killing cell activity. Inappropriate immunologic activity, including inflammation, is a characteristic of many common human disorders. Eicosanoids produced from arachidonic acid have roles in inflammation and regulation of T and B lymphocyte functions. Eicosapentaenoic acid (EPA) also gives rise to eicosanoids and docosahexaenoic acid (DHA) to docosanoids; these may have differing properties to arachidonic acid-derived eicosanoids. EPA and DHA give rise to newly discovered resolvins. Human immune cells are typically rich in arachidonic acid, but arachidonic acid, EPA and DHA contents can be altered through oral administration of those fatty acids. This results in a change pattern of production of eicosanoids and probably also of docosanoids and resolvins, although the latter are not well examined in the human context. Changing the fatty acid composition of immune cells also affects phagocytosis, T-cell signaling and antigen presentation capability. These effects appear to mediated at the membrane level suggesting important roles of fatty acids in membrane order, lipid raft structure and function and membrane trafficking.

Differential immunomodulation with long-chain n-3 PUFA in health and chronic disease.

Abstract: The balance of intake of n-6 and n-3 PUFA, and consequently their relative incorporation into immune cells, is important in determining the development and severity of immune and inflammatory responses. Some disorders characterised by exaggerated inflammation and excessive formation of inflammatory markers have become among the most important causes of death and disability in man in modern societies. The recognition that long-chain n-3 PUFA have the potential to inhibit (excessive) inflammatory responses has led to a large number of clinical investigations with these fatty acids in inflammatory conditions as well as in healthy subjects. The present review explores the presence of dose-related effects of long-chain n-3 PUFA supplementation on immune markers and differences between healthy subjects and those with inflammatory conditions, because of the important implications for the transfer of information gained from studies with healthy subjects to patient populations, e.g. for establishing dose levels for specific applications. The effects of long-chain n-3 PUFA supplementation on ex vivo lymphocyte proliferation and cytokine production by lymphocytes and monocytes in healthy subjects have been studied in twenty-seven, twenty-five and forty-six treatment cohorts respectively, at intake levels ranging from 0.2 g EPA+DHA/d to 7.0 g EPA+DHA/d. Most studies, particularly those with the highest quality study design, have found no effects on these immune markers. Significant effects on lymphocyte proliferation are decreased responses in seven of eight cohorts, particularly in older subjects. The direction of the significant changes in cytokine production by lymphocytes is inconsistent and only found at supplementation levels > or =2.0 g EPA+DHA/d. Significant changes in inflammatory cytokine production by monocytes are decreases in their production in all instances. Overall, these studies fail to reveal strong dose-response effects of EPA+DHA on the outcomes measured and suggest that healthy subjects are relatively insensitive to immunomodulation with long-chain n-3 PUFA, even at intake levels that substantially raise their concentrations in phospholipids of immune cells. In patients with inflammatory conditions cytokine concentrations or production are influenced by EPA+DHA supplementation in a relatively large number of studies. Some of these studies suggest that local effects at the site of inflammation might be more pronounced than systemic effects and disease-related markers are more sensitive to the immunomodulatory effects, indicating that the presence of inflamed tissue or 'sensitised' immune cells in inflammatory disorders might increase sensitivity to the immunomodulatory effects of long-chain n-3 PUFA. In a substantial number of these studies clinical benefits related to the inflammatory state of the condition have been observed in the absence of significant effects on immune markers of inflammation. This finding suggests that condition-specific clinical end points might be more sensitive markers of modulation by EPA+DHA than cytokines. In general, the direction of immunomodulation in healthy subjects (if any) and in inflammatory conditions is the same, which indicates that studies in healthy subjects are a useful tool to describe the general principles of immunomodulation by n-3 PUFA. However, the extent of the effect might be very different in inflammatory conditions, indicating that studies in healthy subjects are not particularly suitable for establishing dose levels for specific applications in inflammatory conditions. The reviewed studies provide no indications that the immunomodulatory effects of long-chain n-3 PUFA impair immune function or infectious disease resistance. In contrast, in some conditions the immunomodulatory effects of EPA+DHA might improve immune function.

Fatty acids and immune function: new insights into mechanisms.

Abstract: Fatty acids are known to play diverse roles in immune cells. They are important as a source of energy, as structural components of cell membranes, as signaling molecules and as precursors for the synthesis of eicosanoids and similar mediators. Recent research has suggested that the localization and organisation of fatty acids into distinct cellular pools has a direct influence on the behaviour of a number of proteins involved in immune cell activation, including those associated with T cell responses, antigen presentation and fatty acid-derived inflammatory mediator production. This article reviews these studies and places them in the context of existing literature in the field. These studies indicate the existence of several novel mechanisms by which altered fatty acid availability can modulate immune responses and impact upon clinical outcomes.

Glucose metabolism in lymphoid and inflammatory cells and tissues

Abstract: PURPOSE OF REVIEW: To examine the role of glucose as a fuel for immune cells and the influence of glucose supply on immune-cell functional responses. RECENT FINDINGS: Immune cells express the insulin receptor and a range of glucose-transporter isoforms. Glucose transporters are responsive to both immune stimulation and insulin. The pattern of glucose-transporter upregulation differs among different types of immune cell. In-vitro studies reveal that both hypo- and hyperglycaemia impair immune-cell functions and promote inflammatory responses. Clamp studies have revealed proinflammatory effects of hyperglycaemia and antiinflammatory and immune-promoting effects of insulin. SUMMARY: Glucose is readily utilized by cells of the immune system and is used to generate energy and biosynthetic precursors. Activation of immune cells is associated with increased glucose utilization and this is facilitated, in part, by increased expression of glucose transporters. Immune cells express the insulin receptor and respond to insulin. Both hypo- and hyperglycaemia impair immune-cell functions and promote inflammatory responses. Insulin therapy in hyperglycaemic subjects may be of benefit through effects of both insulin itself and lowered glucose concentration. Excessive lowering of blood glucose concentration may also be harmful to the immune response

Immunonutrition in surgical and critically ill patients

Abstract: Surgery, trauma, burns and injury induce an inflammatory response that can become excessive and damaging in some patients. This hyperinflammation can be followed by an immunosuppressed state which increases susceptibility to infection. The resulting septic syndromes are associated with significant morbidity and mortality. A range of nutrients are able to modulate inflammation (and the associated oxidative stress) and to maintain or improve immune function. These include several amino acids, antioxidant vitamins and minerals, long-chain n-3 fatty acids and nucleotides. Experimental studies support a role for each of these nutrients in surgical, injured or critically ill patients. There is good evidence that glutamine influences immune function in such patients and that this is associated with clinical improvement. Evidence is also mounting for the use of long-chain n-3 fatty acids in surgical and septic patients, but more evidence of clinical efficacy is required. Mixtures of antioxidant vitamins and minerals are also clinically effective, especially if they include selenium. Their action appears not to involve improved immune function, although an anti-inflammatory mode of action has not been ruled out. Enteral immunonutrient mixtures, usually including arginine, nucleotides and long-chain n-3 fatty acids, have been used widely in surgical and critically ill patients. Evidence of efficacy is good in surgical patients. However whether these same mixtures are beneficial, or should even be used, in critically ill patients remains controversial, since some studies show increased mortality with such mixtures. There is a view that this is due to a high arginine content driving nitric oxide production.

UK Food Standards Agency Workshop Report: the effects of the dietary n-6:n-3 fatty acid ratio on cardiovascular health

Abstract: This report summarises a workshop convened by the UK Food Standards Agency (FSA) on 11 September 2006 to review the results of three FSA-funded studies and other recent research on effects of the dietary n-6:n-3 fatty acid ratio on cardiovascular health. The objective of this workshop was to reach a clear conclusion on whether or not it was worth funding any further research in this area. On the basis of this review of the experimental evidence and on theoretical grounds, it was concluded that the n-6:n-3 fatty acid ratio is not a useful concept and that it distracts attention away from increasing absolute intakes of long-chain n-3 fatty acids which have been shown to have beneficial effects on cardiovascular health. Other markers of fatty acid intake, that more closely relate to physiological function, may be more useful.

Olive oil in parenteral nutrition

Abstract: Purpose of review: A lipid emulsion for use in parenteral nutrition containing a significant proportion of olive oil in place of soybean oil (ClinOleic; Baxter, Maurepas, France) is now available. The purpose of this review is to provide background information about the rationale for this emulsion, to collate and synthesize the literature about it, and to highlight recent studies in which it has been used. Recent findings: ClinOleic offered significant advantage over soybean oil-based emulsions in terms of glucose metabolism in preterm infants. ClinOleic was recently used for the first time in malnourished haemodialysis, trauma and burn patients and was found to be safe and well tolerated. In burn patients ClinOleic was associated with better liver function. Summary: ClinOleic is safe and well tolerated in preterm infants, and in home parenteral nutrition, haemodialysis, trauma and burn patients and may offer advantages with regard to liver function, oxidative stress and immune function. ClinOleic may offer significant advantage over soybean oil-based emulsions in terms of glucose metabolism in preterm infants. More clinical studies of ClinOleic are required and these should include evaluation of oxidative stress markers and immune function as well as of clinical outcomes.

Mechanisms involved in the cytotoxic and cytoprotective actions of saturated versus monounsaturated long-chain fatty acids in pancreatic beta-cells.

Abstract: Long-chain saturated and monounsaturated fatty acids differ in their propensity to induce beta-cell death in vitro with palmitate (C16:0) being cytotoxic, whereas palmitoleate (C16:1n-7) is cytoprotective. We now show that this cytoprotective capacity extends to a poorly metabolised C16:1n-7 derivative, methyl-palmitoleate (0.25 mM palmitate alone: 92 +/- 4% death after 18 h; palmitate plus 0.25 mM methyl-palmitoleate: 12 +/- 2%; P < 0.001). Palmitoleate and its methylated derivative also acted as mitogens in cultured beta-cells (5-bromo-2-deoxyuridine incorporation - control: 0.15 +/- 0.01 units; 0.25 mM palmitoleate: 0.22 +/- 0.01 units; P < 0.05). It has been proposed that alterations in neutral lipid synthesis (particularly triacylglycerol (TAG) formation) might mediate the differential responses to saturated and unsaturated fatty acids and we have examined this proposition. Palmitate and palmitoleate both promoted beta-cell phospholipid remodelling and increased TAG formation (control: 0.9 +/- 0.1 nmol TAG/10(6) cells; 0.25 mM palmitate: 1.55 +/- 0.07; 0.25 mM palmitoleate: 1.4 +/- 0.05; palmitate plus palmitoleate: 2.3 +/- 0.1). By contrast, methyl-palmitoleate failed to influence TAG levels (0.25 mM methyl-palmitoleate alone: 0.95 +/- 0.06 nmol TAG/10(6) cells; methyl-palmitoleate plus palmitate: 1.5 +/- 0.05) or its fatty acid composition in beta-cells exposed to palmitate. The results suggest that monounsaturated fatty acids can promote cell viability and mitogenesis by a mechanism that does not require their metabolism and is independent of alterations in TAG formation.

Immunological Parameters: What Do They Mean?

Abstract: The immune system acts to protect the host from infectious agents that exist in the environment and from other noxious insults. It is constantly active, acting to discriminate "nonself" from "self." The immune system has 2 functional divisions: the innate and the acquired. Both involve various blood-borne factors and cells. A number of methodologies exist to assess aspects of immune function; many of these rely on studying cells in culture ex vivo. There are large interindividual variations in many immune functions even among the healthy. Many factors, including genetics, gender, age, nutrient status, and gut flora, contribute to the observed variation. Individuals with immune responses significantly below "normal" are more susceptible to infectious agents and exhibit increased infectious morbidity and mortality. However, it is not clear how the variation in immune function among healthy individuals relates to variation in susceptibility to infection.

Dietary arachidonic acid: harmful, harmless or helpful?

Abstract: Mammalian cells and tissues contain substantial amounts of the n-6 PUFA arachidonic acid, especially in their membrane phospholipids. For example, platelets from human adults living on a typical Western diet have about 25% phospholipid fatty acids as arachidonic acid, while for human mononuclear cells, neutrophils, erythrocytes, skeletal muscle, cardiac tissue and liver phospholipids, arachidonic acid contents are about 22, 15, 17, 17, 9 and 20% total fatty acids, respectively. This arachidonic acid can have two origins: the diet or endogenous synthesis from a precursor, particularly linoleic acid, which is consumed in fairly high amounts in most diets. Important dietary sources of preformed arachidonic acid are eggs and meat; fish also contain arachidonic acid. Typical intakes of arachidonic acid have been estimated to be between 50 and 300mg/d for adults consuming Western-style diets. The most well-recognised functional role of cell membrane arachidonic acid is as a cell signalling molecule, either in its own right or after its conversion to oxidised derivatives known as eicosanoids. The eicosanoid family of mediators includes prostaglandins, thromboxanes, leukotrienes, lipoxins and hydroxyand hydroperoxy-eicosatetraenoic acids. To form eicosanoids, arachidonic acid is first released from cell membrane phospholipids by phospholipase enzymes. The free arachidonic acid then acts as a substrate for cyclooxygenase, lipoxygenase or cytochrome P450 enzymes, ultimately yielding the various eicosanoid metabolites. These metabolites have well-established roles in many pathological processes including thrombosis, inflammation and immunosuppression. Thus, drugs targeted at eicosanoid synthesis (aspirin, non-steroidal anti-inflammatory drugs, some steroids, cyclooxygenase2 inhibitors) and actions (leukotriene receptor antagonists) have been developed and in some cases are widely used with good efficacy. The idea has developed that, since arachidonic acid-derived mediators are involved in so many pathologies, arachidonic acid itself must be harmful. This notion is compounded by observations that free arachidonic acid is a potent platelet aggregator, induces inflammatory responses and is an immunosuppressant. Finally, the many health benefits of long chain n-3 PUFA frequently involve an ‘antagonism’ of arachidonic acid: long chain n-3 PUFA partly replace arachidonic acid in cell membranes and inhibit arachidonic acid metabolism to eicosanoids. These observations have led to the idea that both arachidonic acid and its eicosanoid derivatives are harmful. This idea is supported by a study with arachidonic acid (6 g/d as an ethyl ester) in healthy human volunteers, which was stopped early (after 3 weeks) because of a dramatic increase in ex vivo platelet aggregation, which prompted concern about a potentially adverse pro-thrombotic action of dietary arachidonic acid. An article in the current issue of the British Journal of Nutrition assesses the impact of increased dietary intake of arachidonic acid in an adult population with high fish intake. This is the first study of arachidonic acid intake in such a population; previous studies in healthy adult human subjects have been conducted in low fish consumers in the USA and in the UK. In this new study, approximately 840mg arachidonic acid/d was consumed by Japanese adults for 4 weeks. Habitual arachidonic acid intake was estimated to range between 110 and 270mg/d with an average of about 175mg/d. This is not unlike typical intakes reported for adults in Western countries. Habitual intakes of EPA and DHA ranged from 42 to 691 and from 98 to 991mg/d, respectively, with average intakes of about 310 and 550mg/d respectively. These are much greater than long chain n-3 PUFA intakes among those subjects involved in studies of arachidonic acid previously (e.g. 90 and 150mg/d for EPA and DHA, respectively). In this new study, the amount of arachidonic acid was increased in serum phospholipids (from 9·6 to 13·7 g/100 g total fatty acids) and TAG (from 1·4 to 2·3 g/ 100 g total fatty acids) with maximum incorporation occurring at 2 weeks of supplementation. The increase in arachidonic acid content of serum phospholipids is consistent with that seen in plasma phospholipids in adults in the UK supplementing their diet with 680mg arachidonic acid/d (from 9·3 to 15·9 g/100 g total fatty acids), in which maximum incorporation occurred at 4 weeks (an earlier time point was not examined). A washout period of 4 weeks resulted in a return of arachidonic acid in serum phospholipids and TAG to levels seen prior to starting supplementation. Again, this is consistent with earlier observations for plasma phospholipids after a 4-week washout period. In the study of Kusumoto et al. there was no effect of supplemental arachidonic acid on blood pressure, serum lipid and glucose concentrations or serum markers of liver function. These findings are consistent with an earlier study conducted in the USA using 1·5 g arachidonic acid/d, which showed no effects on blood lipid or lipoprotein concentrations. However, the main focus of this new study is platelet aggregation. Given this, it is unfortunate that the authors do not report the fatty acid composition of platelet phospholipids. Studies using data across populations with different patterns of PUFA intake have reported that platelet aggregation is highly related to the arachidonic acid and EPA contents of platelets. In this new study, maximal aggregation of platelets in response to ADP, collagen or arachidonic acid and platelet sensitivity to ADP or collagen were not affected by dietary arachidonic acid supplementation. Thus, the main conclusion from this new study is that increasing arachidonic acid intake by 840mg/d does not British Journal of Nutrition (2007), 98, 451–453 doi: 10.1017/S0007114507761779 q The Author 2007

Decreased tumor growth in Walker 256 tumor-bearing rats chronically supplemented with fish oil involves COX-2 and PGE2 reduction associated with apoptosis and increased peroxidation.

Abstract: Many studies have shown that addition of fish oil (FO) to the diet reduces tumor growth but the mechanism(s) of action involved is (are) still unknown. In this study, we examine some possible mechanisms in tumor-bearing rats chronically supplemented with FO. Male Wistar rats (21 days old) were fed with regular chow and supplemented with coconut or FO (1g/kg body weight) until they reached 70 days of age. Then, they were inoculated with a suspension of Walker 256 ascitic tumor cells (2 x 10(7)ml) and after 14 days they were killed. Supplementation with FO resulted in significantly lower tumor weight, greater tumor cell apoptosis, lower ex vivo tumor cell proliferation, a higher tumor content of lipid peroxides, lower expression of cyclooxygenase-2 (COX-2) in tumor tissue and a lower plasma concentration of prostaglandin E2 than observed in rats fed regular chow or supplemented with coconut oil. These results suggest that reduction of tumor growth by FO involves an increase in apoptosis and of lipid peroxidation in tumor tissue, with a reduction in tumor cell proliferation ex vivo, COX-2 expression and PGE2 production. Thus, FO may act simultaneously through multiple effects to reduce tumor growth. Whether these effects are connected through a single underlying mechanism remains to be seen.

The effect of altering the 20:5n-3 and 22:6n-3 content of a meal on the postprandial incorporation of n-3 polyunsaturated fatty acids into plasma triacylglycerol and non-esterified fatty acids in humans

Abstract: Previous studies suggest that consuming meals containing large amounts of fish oil is associated with selective postprandial incorporation of 20:5n-3 and 22:6n-3 into plasma non-esterified fatty acids (NEFA). We investigated the effect of consuming meals containing different amounts of 20:5n-3 and 22:6n-3 comparable to dietary habits of western populations on the postprandial incorporation of 18:3n-3, 20:5n-3 and 22:6n-3 into plasma triacylglycerol (TAG) and NEFA over 6h in middle aged subjects. 20:5n-3 incorporation into plasma TAG was greater than 22:6n-3 irrespective of the test meal. Conversely, 22:6n-3 incorporation into plasma NEFA was greater than 20:5n-3, irrespective of the test meal. There was no effect of the amount of 20:5n-3+22:6n-3 in the test meal on the 18:3n-3 incorporation into plasma TAG or NEFA. These findings suggest differential metabolism of 20:5n-3 and 22:6n-3 in the postprandial period when consumed in amounts typical of western dietary habits.

Dietary Supplementation with Fish Oil Modifies the Ability of Human Monocytes to Induce an Inflammatory Response

Abstract: Monocytes/macrophages are key orchestrators of inflammation and are involved in the pathogenesis of chronic inflammatory disorders, including atherosclerosis. (n-3) Fatty acids, found in fish oil, have been shown to have protective effects in such disorders. To investigate possible modes of action, we used a monocyte:endothelial cell (EC) coculture model to investigate the pro-inflammatory potential of monocytes. Monocytes were isolated from the blood of donors with peripheral arterial disease (PAD) or control donors, before and after a 12-wk supplementation of their diet with fish oil. The monocytes were cultured with human umbilical vein EC (HUVEC) for 24 h, after which the ability of the HUVEC to recruit flowing neutrophils was tested. Monocytes from either group of donors stimulated the EC to support the adhesion and migration of neutrophils. Fish oil supplementation reduced the potency of monocytes from normal subjects, but not those from patients with PAD, to induce recruitment. Concurrent medication may have acted as a complicating factor. On subgroup analysis, only those free of medication showed a significant effect of fish oil. Responses before or after supplementation were not closely linked to patterns of secretion of cytokines by cultured monocytes, tested in parallel monocultures. These results suggest that fish oil can modulate the ability of monocytes to stimulate EC and that this might contribute to their protective effects against chronic inflammatory disorders. Benefits, however, may depend on existing medical status and on other treatments being received.

Fish oil induced increase in walking distance, but not ankle brachial pressure index, in peripheral arterial disease is dependent on both body mass index and inflammatory genotype

Abstract: Peripheral arterial disease (PAD) is an atherosclerotic disease. Evidence suggests that atherosclerosis is an inflammatory condition and long chain n-3 fatty acids, found in oily fish and fish oils, have been shown to reduce inflammation. Genetic and lifestyle factors such as body mass index (BMI) also influence inflammation. In this study we have examined the effect of fish oil in patients with claudication secondary to PAD. Fish oil supplementation, providing 1g EPA and 0.7 g DHA per day for 12 weeks, increased walking distance on a treadmill set at 3.2 km/h with a 7% incline. Walking distance to first pain increased from 76.2+/-8.5 m before fish oil to 140.6+/-25.5 m after fish oil (mean+/-SEM, p=0.004) and total distance walked increased from 160.0+/-21.5 m before fish oil to 242.1+/-34.5 m after fish oil (p=0.002). Fish oil supplementation also improved ankle brachial pressure index (ABPI) from 0.599+/-0.017 before fish oil to 0.776+/-0.030 after fish oil (p<0.001). The increase in walking distance was dependent on both BMI and genotype for single nucleotide polymorphisms in the genes encoding the pro-inflammatory cytokines tumour necrosis factor-alpha and interleukin (IL)-1beta and the anti-inflammatory cytokine IL-10 (detected using amplification refractory mutation system polymerase chain reaction). Neither BMI nor any of the genotypes examined affected the ability of fish oil to increase ABPI. The mechanisms by which fish oil affects walking distance and ABPI do not appear to be the same.

Membrane fatty acids, oxidative burst and phagocytosis after enrichment of P388D1 monocyte/macrophages with essential 18-carbon fatty acids.

Abstract: The fatty acid composition of cell membranes can be modified in cell culture. The role of different fatty acid families in modulating phagocytosis and oxidative burst is not clear and therefore the influence of 18-carbon polyunsaturated fatty acids (PUFA) on these processes was examined. The mouse monocyte/macrophage line P388D1 was cultured in medium supplemented with 2 or 20 micromol/l 18:2n-6 (linoleic acid; LA) or 18:3n-3 (alpha-linolenic acid; LNA) and fatty acid enrichment of the cells was tested after 8 days. The macrophages were activated with phorbol ester in order to promote oxidative burst and intracellular dihydrorhodamine oxidation was determined. To test phagocytosis capacity uptake of fluorescence-labeled Escherichia coli was determined. Activation of the transcription factor nuclear factor (NF)-kappaB was also determined. Cells grown in medium with 20 micromol/l LA contained 2- to 3-fold more n-6 PUFA including 4-fold more arachidonic acid. Cells grown in medium with 20 micromol/l LNA contained 4-fold more n-3 PUFA. Both LA and LNA enhanced phagocytosis and decreased oxidative burst, with little difference between the fatty acids. NF-kappaB activation at 1 h post-stimulation was not affected by adding LA or LNA to the culture medium. We conclude that the fatty acid composition of macrophages influences their ability to phagocytose and mount oxidative burst.

Polyunsaturated fatty acids alter the rules of engagement

Abstract: Evaluation of: Shaikh SR, Edidin M: Immunosuppressive effects of polyunsaturated fatty acids on antigen presentation by HLA class I molecules. J. Lipid Res. 48, 127–138 (2007). This study is the first report of the effect polyunsaturated fatty acids have on the expression of human leukocyte antigen (HLA) class I on the surface of antigen-presenting cells. Arachidonic acid (AA) and docosahexenoic acid (DHA) decreased expression of HLA class I on the surface of B lymphoblasts and this was associated with decreased lysis of those cells by cytotoxic T lymphocytes. AA and DHA decreased surface appearance of new class I molecules by slowing their flow from the endoplasmic reticulum to the Golgi. AA and DHA treatment of target B lymphoblasts also decreased the ability of cytotoxic T lymphocytes to form conjugates with them, suggesting an impairment of the close interaction between the antigen-presenting cell and T lymphocyte that is independent of HLA class I expression. AA and DHA-induced inhibition of HLA clas...

Lipid Rafts―Composition, characterization, and controversies (n-3) PUFA alter raft lipid composition and decrease epidermal growth factor receptor levels in lipid rafts of human breast cancer cells1,2 .Commentary

Abstract: To determine the mechanism by which the (n-3) fatty acids (FA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) decrease proliferation and induce apoptosis in MDA-MB-231 human breast cancer cells, we examined the effects of EPA and DHA on the lipid composition of lipid rafts as well as epidermal growth factor receptor (EGFR) raft localization and phosphorylation. (n-3) FA (a combination of EPA and DHA) inhibited (P < 0.05) the growth of MDA-MB-231 cells by 48-62% in the presence and absence, respectively, of linoleic acid (LA). More EPA and DHA were incorporated into lipid rafts isolated from MDA-MB-231 cells after treatment with (n-3) FA compared with cells treated with LA (P < 0.05). EPA and DHA treatment decreased (P< 0.05) lipid raft sphingomyelin, cholesterol, and diacylglycerol content and, in the absence of LA, EPA and DHA increased (P< 0.05) raft ceramide levels. Furthermore, there was a marked decrease in EGFR levels in lipid rafts, accompanied by increases in the phosphorylation of both EGFR and p38 mitogen-activated protein kinase (MAPK), in EPA+DHA-treated cells (P < 0.05). As sustained activation of the EGFR and p38 MAPK has been associated with apoptosis in human breast cancer cells, our results indicate that (n-3) FA modify the lipid composition of membrane rafts and alter EGFR signaling in a way that decreases the growth of breast tumors.

Review Articles Immune modulation by parenteral lipid emulsions 1,2

Abstract: Totalparenteralnutritionisthefinaloptionfornutritionalsupportof patientswithsevereintestinalfailure.Lipidemulsionsconstitutethe main source of fuel calories and fatty acids (FAs) in parenteral nutrition formulations. However, adverse effects on patient outcomes have been attributed to the use of lipids, mostly in relation to impaired immune defenses and altered inflammatory responses. Overtheyears,thisissuehasremainedinthelimelight,alsobecause technical advances have provided no safeguard against the most daunting problems, ie, infectious complications. Nevertheless, numerous investigations have failed to produce a clear picture of the immunologic characteristics of the most commonly used soybean oil–derived lipid emulsions, although their high content of n6 polyunsaturated FAs (PUFAs) has been considered a drawback because of their proinflammatory potential. This concern initiated the development of emulsions in which part of the n6 FA component is replaced by less bioactive FAs, such as coconut oil (rich in medium-chain saturated FAs) or olive oil (rich in the n9 monounsaturated FA oleic acid). Another approach has been to use fish oil (rich in n3 PUFA), the FAs of which have biological activities different from those of n6 PUFAs. Recent studies on the modulation of host defenses and inflammation by fish-oil emulsions have yielded consistent data, which indicate that these emulsions may provide a tool to beneficially alter the course of immune-mediated conditions.AlthoughmostoftheselipidshavenotyetbecomeavailableontheUSmarket,thisreviewsynthesizesavailableinformation on immunologic characteristics of the different lipids that currently can be applied via parenteral nutrition support. Am J Clin Nutr 2007;85:1171–84.