Supplementation with omega3 polyunsaturated fatty acids and all-rac alpha-tocopherol alone and in combination failed to exert an anti-inflammatory effect in human volunteers.

Metabolism. 2004 Feb;53(2):236-40.

Vega-Lopez S, Kaul N, Devaraj S, Cai RY, German B, Jialal I.

Laboratory for Atherosclerosis and Metabolic Research, University of California, Davis, Medical Center, Sacramento, CA, USA.

There is growing evidence supporting the importance of inflammation in all stages of atherosclerosis. While both omega-3 polyunsaturated fatty acids (n3PUFA) and the lipid-soluble antioxidant alpha-tocopherol (AT) have been shown to independently have significant anti-inflammatory effects, there is paucity of data examining the effect of n3PUFA alone and in combination with AT on markers of inflammation and monocyte function. Therefore, we tested the effect of n3PUFA alone, all-rac (synthetic) AT alone, and the combination on markers of inflammation and monocyte function. Healthy nonsmoking volunteers were randomly assigned to 1 of 4 groups (n = 20 per group): 1.5 g/d n3PUFA, 800 IU/d AT, 1.5 g n3PUFA + 800 IU/d AT, or placebo in a parallel double-blinded study. Compared to baseline, 12 weeks of supplementation resulted in no changes in plasma lipids regardless of treatment. Plasma AT was significantly increased only in those groups that received AT (P <.0001). Similarly, groups receiving n3PUFA showed a significant increase in plasma docosahexaenoic acid (P <.0001). No significant within- or between-group differences were found for plasma levels of high-sensitivity C-reactive protein (hsCRP). Furthermore, there were no differences in monocyte proinflammatory cytokine release (interleukin [IL]-1beta, tumor necrosis factor [TNF]-alpha and IL-6) after activation with monocyte chemotactic protein-1 (MCP-1). In conclusion, supplementation with n3PUFA and all-rac AT at these doses is not anti-inflammatory.

An omega-3 polyunsaturated fatty acid concentrate increases plasma high-density lipoprotein 2 cholesterol and paraoxonase levels in patients with familial combined hyperlipidemia.

Metabolism. 2004 Feb;53(2):153-8.

Calabresi L, Villa B, Canavesi M, Sirtori CR, James RW, Bernini F, Franceschini G.

Center E. Grossi Paoletti, Department of Pharmacological Sciences, University of Milano, Milan, Italy.

A remarkable reduction of plasma concentrations of high-density lipoproteins (HDL), especially of the HDL(2) subfraction, is one of the typical lipoprotein alterations found in patients with familial combined hyperlipidemia (FCHL). Fourteen FCHL patients received 4 capsules daily of Omacor (an omega-3 polyunsaturated fatty acid [omega3 FA] concentrate providing 1.88 g of eicosapentaenoic acid [EPA] and 1.48 g of docosahexaenoic acid [DHA] per day; Pronova Biocare, Oslo, Norway) or placebo for 8 weeks in a randomized, double-blind, crossover study. Plasma triglycerides were 44% lower, and LDL cholesterol and apoliporpotein (apo)B were 25% and 7% higher after Omacor than placebo. HDL cholesterol was higher (+8%) after Omacor than placebo, but this difference did not achieve statistical significance. Omacor caused a selective increase of the more buoyant HDL(2) subfraction; plasma HDL(2) cholesterol and total mass increased by 40% and 26%, respectively, whereas HDL(3) cholesterol and total mass decreased by 4% and 6%. Both HDL(2) and HDL(3) were enriched in cholesteryl esters and depleted of triglycerides after Omacor. No changes were observed in the plasma concentration of major HDL apolipoproteins, LpA-I and LpA-I:A-II particles, lecithin:cholesterol acyltransferase (LCAT), and cholesteryl ester transfer protein (CETP). The plasma concentration of the HDL-bound antioxidant enzyme paraoxonase increased by 10% after Omacor. Omacor may be helpful in correcting multiple lipoprotein abnormalities and reducing cardiovascular risk in FCHL patients.

Dietary intake of n-3, n-6 fatty acids and fish: relationship with hostility in young adults--the CARDIA study.

Eur J Clin Nutr. 2004 Jan;58(1):24-31.

Iribarren C, Markovitz JH, Jacobs DR Jr, Schreiner PJ, Daviglus M, Hibbeln JR.

Division of Research, Kaiser Permanente, Oakland, CA, USA. cgi@dor.kaiser.org

BACKGROUND: Hostility has been shown to predict both the development and manifestation of coronary disease. Examining the inter-relation of dietary intake of fish and of polyunsaturated (n-3 and n-6) essential fatty acids with hostility may provide additional insights into the cardioprotective effect of dietary fish and polyunsaturated fatty acids. OBJECTIVE: To examine the association of dietary n-3, n-6 fatty acids and fish with level of hostility in a sample of 3581 urban white and black young adults. DESIGN: Cross-sectional observational study as part of an ongoing cohort study. A dietary assessment in 1992-1993 and measurement of hostility and other covariates in 1990-1991 were used in the analysis. RESULTS: The multivariate odds ratios of scoring in the upper quartile of hostility (adjusting for age, sex, race, field center, educational attainment, marital status, body mass index, smoking, alcohol consumption and physical activity) associated with one standard deviation increase in docosahexaenoic acid (DHA, 22:6) intake was 0.90 (95% CI=0.82-0.98; P=0.02). Consumption of any fish rich in n-3 fatty acids, compared to no consumption, was also independently associated with lower odds of high hostility (OR=0.82; 95% CI=0.69-0.97; P=0.02). CONCLUSIONS: These results suggest that high dietary intake of DHA and consumption of fish rich in n-3 fatty acids may be related to lower likelihood of high hostility in young adulthood. The association between dietary n-3 fatty acids and hostile personality merits further research.

Clinical potential of omega-3 fatty acids in the treatment of schizophrenia.

CNS Drugs. 2003;17(15):1081-91.

Emsley R, Oosthuizen P, van Rensburg SJ.

Department of Psychiatry, Faculty of Health Sciences, University of Stellenbosch, Tygerberg 7505, Cape Town, South Africa. rae@sun.ac.za

The phospholipids in the neuronal membranes of the brain are rich in highly unsaturated essential fatty acids (EFAs). It has been hypothesised that abnormalities of phospholipid metabolism are present in patients with schizophrenia and that the EFAs omega-3 polyunsaturated fatty acids, and eicosapentaenoic acid (EPA) in particular, may have a role in treating this illness. Considerable preclinical and clinical evidence provides support for this proposal. An epidemiological study reported a better outcome for patients with schizophrenia in countries where the diet is rich in unsaturated fatty acids. Evidence of abnormalities of EFAs has been found in erythrocyte membranes and cultured skin fibroblasts of patients with schizophrenia, and abnormal retinal function and niacin skin flush tests (markers of omega-3 polyunsaturated fatty acid depletion) have also been reported. Case reports and an open-label clinical trial reported efficacy for EPA in schizophrenia. Four randomised, controlled trials of EPA versus placebo as supplemental medication have now been reported. Two of these trials showed significant benefit with EPA on the positive and negative symptom scale total scores, whereas the other two did not show any effects on this primary efficacy measure. One study also reported a beneficial effect on dyskinesia. In the only published trial in which EPA was used as monotherapy versus placebo in schizophrenia, some evidence was found to suggest antipsychotic activity. Taken together, there is considerable evidence to suggest abnormalities of EFAs in cell membranes of patients with schizophrenia, and there is preliminary evidence that EPA is an effective adjunct to antipsychotics.

Health benefits and potential risks related to consumption of fish or fish oil.

Regul Toxicol Pharmacol. 2003 Dec;38(3):336-44.

Sidhu KS.

Division of Environmental and Occupational Epidemiology, Michigan Department of Community Health, 3423 North Martin Luther King Jr. Blvd., P.O. Box 30195, Lansing, MI 48909, USA. sidhuk@msu.edu

The nutritional benefits of fish consumption relate to the utilization of proteins of high biological value, as well as certain minerals and vitamins that fish provide. Fish or fish oil contains omega-3 polyunsaturated fatty acids (PUFAs) that appear to play several useful roles for human health. Conversely, some carcinogenic contaminants are also stored in the adipose tissue of fish. The objective of this paper is to evaluate the potential health benefits and risks related to the consumption of fish or fish oil. Health benefits related to the consumption of fish or omega-3 PUFAs were obtained by an extensive literature search. Potential health risks related to carcinogenic contaminants (e.g., dioxin, PCB, etc.) in fish were estimated using the U.S. EPA-approved cancer risk assessment guidelines. Potential health risk estimates were evaluated by comparing them with the acceptable excess risk level of 10(-6)-10(-4). Scientific data indicate that the consumption of fish or fish oil containing omega-3 PUFAs reduces the risk of coronary heart disease, decreases mild hypertension, and prevents certain cardiac arrhythmias and sudden death. Risk estimates in humans for carcinogenic environmental contaminants in fish ranged from an excess risk level of 3x10(-6)-9x10(-4). These risk estimates appeared to meet the acceptable excess risk level criteria. Therefore, consumption of fish in accordance with the State of Michigan Fish Advisory Guidelines is safe and should be encouraged. The top 11 fish species [e.g., sardines, mackerel, herring (Atlantic and Pacific), lake trout, salmon (Chinook, Atlantic, and Sockeye), anchovy (European), sablefish, and bluefish] provide an adequate amount of omega-3 PUFAs (2.7-7.5g/meal) and appear to meet the nutritional recommendation of the American Heart Association.

Fish oils modulate blood pressure and vascular contractility in the rat and vascular contractility in the primate

Blood Press (NORWAY) May 1995, 4 (3) p177-86

The effect of dietary fish oils on development of hypertension and vascular response in vitro were studied in rats and a primate. Dietary fish oils (MaxEPA and an n-3 ethyl ester concentrate of higher EPA and DHA content) were administered to spontaneously hypertensive (SHR), stroke-prone spontaneously hypertensive (SHR-SP) and a backcross of SHR and Wistar Kyoto (SHR/WKY) rats from 4-16 weeks of age. Blood pressure was monitored during the feeding period and vascular responses measured in the aorta and mesenteric vascular bed in vitro. Depending on the strain of rat used and the composition of the fish oil the attenuation in blood pressure was 10-26 mmHg. Fish oils attenuated the response mediated by sympathetic nerve stimulation or intralumenal norepinephrine in the perfused mesenteric vascular bed preparation from the SHR. This attenuation was more pronounced for fish oils enriched with eicosapentaenoic acid and docosahexaenoic acid and was more prominent in the SHR and SHR/WKY backcross than it was in the SHR-SP. Prostanoid synthesis or nitric oxide modulation of alpha-adrenoceptor responses were shown not to be involved in the attenuation of vascular responses produced by fish oil. The maximum contraction of aortic ring preparations in response to norepinephrine (NE) was significantly smaller in SHR than WKY rats fed olive oil and for SHR rats maintained on fish oils the contraction was close to WKY olive oil values. Evidence was obtained also for a modulation of vasoconstrictor responses by dietary fish oils in the perfused mesenteric bed of the marmoset monkey.

Fish oil and other nutritional adjuvants for treatment of congestive heart failure

Medical Hypotheses (United Kingdom), 1996, 46/4 (400-406)

Published clinical research, as well as various theoretical considerations, suggest that supplemental intakes of the 'metavitamins' taurine, coenzyme Q10, and L-carnitine, as well as of the minerals magnesium, potassium, and chromium, may be of therapeutic benefit in congestive heart failure. High intakes of fish oil may likewise be beneficial in this syndrome. Fish oil may decrease cardiac afterload by an antivasopressor action and by reducing blood viscosity, may reduce arrhythmic risk despite supporting the heart's beta-adrenergic responsiveness, may decrease fibrotic cardiac remodeling by impeding the action of angiotensin II and, in patients with coronary disease, may reduce the risk of atherothrombotic ischemic complications. Since the measures recommended here are nutritional and carry little if any toxic risk, there is no reason why their joint application should not be studied as a comprehensive nutritional therapy for congestive heart failure.

Dietary (n-3) fatty acids increase superoxide dismutase activity and decrease thromboxane production in the rat heart.

Luostarinen R.; Wallin R.; Saldeen T.

Nutrition Research (USA), 1997, 17/1 (163-175)

The aims of the present studies were to examine the effects of fish oil (containing (n-3) polyunsaturated fatty acids) on myocardial thromboxane and prostacyclin production, superoxide dismutase (SOD) activity and malondialdehyde (MDA) production in the rat. Male rats were fed standard pellet diets and the same diets enriched with 7% (w/w) stabilized fish oil or 7% butter (saturated fat) for 2-6 wk. Myocardial production of thromboxane was lower in rats given fish oil than in those fed standard pellets (P < 0.01) or saturated fat (P < 0.05) and the prostacyclin/thromboxane ratio was higher than in rats fed standard pellets (P < 0.05). Myocardial SOD activity was higher in rats fed stabilized fish oil than in those given saturated fat (P < 0.05). Supplementation of the stabilized fish oil with extra vitamin E did not have any major effect on thromboxane and prostacyclin production or SOD activity. The percentage of arachidonic acid in the myocardial phospholipids was lower (P < 0.001) during fish oil than during saturated fat feeding, with no modifying effect of vitamin E supplementation. Feeding with the stabilized fish oil did not alter the myocardial alpha-tocopherol concentration, but the myocardial MDA concentration in vitro was higher (P < 0.01) than after feeding with saturated fat. Supplementation of the stabilized fish oil with extra vitamin E resulted in a higher alpha-tocopherol (P < 0.05) and lower MDA concentration (P < 0.05) in the myocardium compared to the unsupplemented fish oil. Plasma MDA concentration was not changed by fish oil feeding. In conclusion, fish oil feeding resulted in higher myocardial SOD activity and lower thromboxane production. These changes may be contributory mechanisms underlying the antiarrhythmic effect of fish oil.

Effects of n-3 fatty acids and fenofibrate on lipid and hemorrheological parameters in familial dysbetalipoproteinemia and familial hypertriglyceridemia.

Otto C.; Ritter M.M.; Soennichsen A.C.; Schwandt P.; Richter W.O.

Medical Department II, Klinikum Grosshadern, University of Munich, Marchioninistrasse 15, D-81366 Munich Germany

Metabolism: Clinical and Experimental (USA), 1996, 45/10 (1305-1311)

There is increasing evidence that hemorrheological abnormalities are associated with an enhanced risk of atherosclerosis. The n-3 fatty acids (n- 3-FA) have been shown to have beneficial effects on atherosclerosis in patients with dyslipoproteinemias. We studied 23 patients with elevated plasma triglycerides to evaluate the influence of fish oil and fenofibrate therapy on hemorrheological parameters (15 patients with familial hypertriglyceridemia (FHTG) and eight with familial dysbatalipoproteinemia (FDL)). The patients (one woman and 22 men aged 45.7 plus or minus 2.0 years) were treated with increasing doses of n-3-FA (1.8 to 3.6 g/d: 0.9 to 1.8 g eicosapentaenoic acid and 0.6 to 1.2 g docosahexaenoic acid) for 8 weeks. Lipid parameters, whole-blood viscosity at different shear rates, plasma viscosity, fibrinogen concentration, and red blood cell aggregation (RCA) were measured at baseline and at weeks 2, 4, g (end of n-3-FA therapy), and 12. Compliance was ensured by measuring plasma concentrations of eicosapentaenoic acid and docosahexaenoic acid. After 12 weeks, patients began treatment with fenofibrate (250 mg daily); investigations were performed again at week 20. Total triglycerides (from 6.90 plus or minus 1.70 to 3.61 plus or minus 0.78 mmol/L in FDL and 7.44 plus or minus 1.50 to 4.15 plus or minus 0.55 in FHTG), very-low- density lipoprotein (VLDL) triglycerides, and VLDL cholesterol were significantly decreased with n-3-FA therapy in both groups (P < .05). In FHTG, low-density lipoprotein (LDL) cholesterol increased significantly (from 2.75 plus or minus 0.28 to 3.97 plus or minus 0.35 mmol/L, P < .01); in FDL, total cholesterol decreased (from 9.76 plus or minus 1.32 to 7.34 plus or minus 1.07 mmol/L, P < .05). No significant changes were observed in hemorrheological parameters, except for reduced RCA with 3.6 g n-3-FA in FHTG. However, with fenofibrate therapy, in addition to comparable lipoprotein changes seen with fish oil, fibrinogen levels and plasma and blood viscosity decreased in patients with FDL. We conclude that n-3-FA and fenofibrate have comparable effects on lipid parameters in patients with FDL and FHTG. Because of additional beneficial effects on hemorrheological parameters, fenofibrate may be preferred for the treatment of FDL.

Repeated fasting and refeeding with 20:5, n-3 Eicosapentaenoic Acid (EPA): A novel approach for rapid fatty acid exchanges and its effect on blood pressure, plasma lipids and hemostasis.

Journal of Human Hypertension (United Kingdom), 1996, 10/SUPPL. 3 (S135-S139)

Yosefy C.; Viskoper J.R.; Varon D.; Ilan Z.; Pilpel D.; Lugassy G.; Schneider R.; Adan Y.; Raz A.

Department of Medicine B, Barzilai Medical Center, Ashkelon Israel

Twenty hypertensive subjects participated in three clinical trials of 13 days each, to examine the effects of Alsepa fish oil (20:5, n-3 eicosapentaenoic acid (EPA) 180 mg, and 22:6 n-3 docosahexaenoic acid (DHA) 120 mg) on n-3 for n-6 polyunsaturated fatty acids (PUFA) exchange on serum phospholipids, blood pressure (BP), triglycerides (TG) and primary hemostasis. After 13 days, plasma phospholipids showed an increase in Sigman-3 (EPA and DHA) from 2.0 to 5.9% (P < 0.01), and a decrease in Sigman-6 (arachidonic acid and linoleic acid) from 29.8 to 22.6% (P < 0.01). A concomitantly significant reduction in systolic BP (SBP) (158.7 plus or minus 23.8 mmHg to 146.5 plus or minus 17.0 mmHg, P = 0.04), and diastolic BP (DBP) (80.8 plus or minus 8.4 mmHg to 72.9 plus or minus 14.9 mmHg, P = 0.04) as well as a significant decrease in platelet adhesion and aggregation on extra cellular matrix measured as a percentage of surface coverage (11.9 plus or minus 4.8% to 4.2 plus or minus 3.2%, P = 0.0001) was observed. In addition, a significant reduction in baseline dependent To was observed; the higher the baseline level TG, the more pronounced the reduction (average 159.2 plus or minus 74.6 mg% to 108.0 plus or minus 46.1 mg%, P = 0.001). No change was observed in total cholesterol, high and low density lipoprotein (HDL, LDL), platelet and fibrinogen. Repeated fasting and refeeding with fish oil facilitated plasma exchange of n-3 for n-6 PUFA, improved BP, clinical metabolic parameters and lowered platelet reactivity in the vessel wall (primary hemostasis). In severe and life-threatening situations, the beneficial effects of fish oil should be considered for rapid exchange of n-3 for n-6 PUFA. In this study we describe a novel approach for rapid fatty acid exchange by fasting/refeeding with fish oil supplementation, as well as improved BP, plasma lipids and primary hemostasis. Further research is required on the therapeutic use of fish oils and the physiological mechanisms involved in fatty acid exchange.

Interactions between dietary fat, fish, and fish oils and their effects on platelet function in men at risk of cardiovascular disease.

Arteriosclerosis, Thrombosis, and Vascular Biology (USA), 1997, 17/2 (279-286)

Mori T.A.; Beilin L.J.; Burke V.; Morris J.; Ritchie J.

Dr. T.A. Mori, University Department of Medicine, Medical Research Foundation Building, Box X2213 GPO, Perth, WA 6001 Australia

Recent studies have suggested that omega3-fats of marine origin may have a protective role in heart disease. This study aimed to compare the effects of fish or fish oil, in the setting of a high- or low fat diet, on platelet aggregation and platelet thromboxane in men with increased risk of cardiovascular disease. One hundred twenty men who were nonsmokers, 30 to 60 years old, with mildly elevated blood pressure and cholesterol were randomly allocated to one of five high-fat (40% of daily energy) or two low-fat (30%) groups for 12 weeks. The five high fat groups took either 6 or 12 fish oil capsules daily; fish a combination of fish and fish oil; or placebo capsules. The two low-fat groups took either fish or placebo capsules. Fish meals provided 1.3 g of eicosapentaenoic acid daily, equivalent to 6 fish oil capsules, and contained an average of 3.65 g/d of omega3-fatty acids. Multiple regression analysis of the combined groups showed that all groups taking omega3- fatty acids reduced platelet aggregation to both collagen (P<.0001) and platelet activating factor (PAF) (P<.05) and platelet thromboxane B2 responses (P<.05) to collagen-induced aggregation. The low-fat diet alone had no effect on PAF-induced platelet aggregation and only a small effect on platelet responses to collagen (P<.05). Platelet aggregation responses to PAF were reduced more by fish oil than fish in a high-fat diet, whereas fish had a greater effect when part of a low-fat rather than a high-fat diet. There was no significant difference in collagen-induced aggregation or platelet thromboxane between fish and fish oils on a high or low fat intake. In conjunction with our previous findings of improvements in lipoproteins, blood pressure, and heart rate in this population, these results on platelet function suggest that dietary omega3-fatty acids incorporated into a low rather than a high-fat diet have a wider spectrum of more favorable effects on cardiovascular risk factors.

Prevalence of essential fatty acid deficiency in patients with chronic gastrointestinal disorders.

Metabolism (UNITED STATES) Jan 1996, 45 (1) p12-23

Patients with chronic intestinal disorders causing malabsorption, nutritional losses through diarrhea, or catabolic illness would be expected to have essential fatty acid (EFA) deficiency (EFAD), but such deficiency has not been demonstrated in patients treated in accordance with the prevailing standard of care. We studied plasma fatty acid patterns of 56 reference or control subjects and 47 patients with chronic intestinal disorders (mostly Crohn's disease) using high-resolution capillary column gas-liquid chromatography. Patients exhibited a shift in fatty acid metabolism similar to that previously shown to be associated with EFAD. Compared with control subjects, patients had (1) decreased polyunsaturated fatty acid (PUFA) levels (43.7% v 50.4%, P < .0001), (2) increased monounsaturated fatty acid (MUFA) levels (25.8% v 22.0%, P < .0001), (3) higher ratios of mead (20:3 omega 9) to arachidonic (20:4 omega 6) acid (0.020 v 0.013, P < .04), and (4) lower concentrations of total (214 v 284 mg/dL, P < .01), saturated ([SFA] 63 v 75 mg/dL, P < .001), MUFA (56 v 63 mg/dL, P < .001), and PUFA (93 v 143 mg/dL, P < .001). Patients had metabolic shifts toward increased production of MUFA and an increased ratio of derivatives to precursors of omega 6 fatty acids, shifts that occur when cells are EFA-deficient. More than 25% of the patients had biochemical evidence of EFAD according to at least one criterion. Optimal diagnosis requires a concurrent evaluation of concentrations of fatty acids in plasma and in lipoproteins (percent fatty acids). On indices of EFA status that depend on percents, ratios, or concentrations of fatty acids or on the production of abnormal fatty acids, the patients were between patients with severe whole-body EFAD and healthy subjects, a state referred to as absolute EFA insufficiency. Patients with chronic intestinal disease should be evaluated for likely EFA deficiencies and imbalances, and treated with substantial amounts of supplements rich in EFAs, such as oral vegetable and fish oils, or intravenous lipids if necessary.

The effect of polyunsaturated fatty acids on the progress of cachexia in patients with pancreatic cancer

Nutrition (USA), 1996, 12/1 SUPPL. (S27-S30)

Cachexia is common in patients with pancreatic cancer and has been associated with persistent activation of the hepatic acute phase response and increased energy expenditure. Fatty acids have been shown to have anticachectic effects in animal models and to reduce inflammatory mediators in healthy subjects and patients with chronic inflammatory disease. Eighteen patients with unresectable pancreatic cancer received dietary supplementation orally with fish oil capsules (1 g each) containing eicosapentaenoic acid 18% and docosahexaenoic acid 12%. Anthropometric measurement, body composition analysis, and measurement of resting energy expenditure and serum C-reactive protein were performed before and after supplementation with a median of 12 g/day of fish oil. Patients had a median weight loss of 2.9 kg/month (IQR 2- 4.6) prior to supplementation. At a median of 3 months after commencement of fish oil supplementation, patients had a median weight gain of 0.3 kg/month (IQR 0.-0.5) (p < 0.002). Changes in weight were accompanied by a temporary but significant reduction in acute phase protein production (p < 0.002) and by stabilisation of resting energy expenditure. This study suggests a component fish oil, perhaps EPA, merits further investigation in the treatment of cancer cachexia.

Modulation of antioxidant enzymes and programmed cell death by n-3 fatty acids

Lipids (USA), 1996, 31/3 SUPPL. (S91-S96)

Studies from our laboratory indicate that n-3 (fish oil, FO) lipids at 10% (w/w) in a nutritionally adequate, semi-purified diet, and supplemented with equal levels of antioxidants, extended the life span of lupus-prone (NZB/NZW)F1 (B/W) female mice as compared to n-6 (corn oil, CO) lipids. The early rise of autoimmune disease in CO-fed mice was closely linked to the loss of T-cell function. Both IL-2 production and IL-2 receptor expression were reduced due to the loss of naive T-cells and a rise in memory T-cells. Proliferative response to both mitogens and superantigens (staphylococcal enterotoxins A and B) was higher in FO-fed 6.5-mon-old mice. These changes paralleled decreased PGE2 production by splenic cells from FO-fed mice. Analysis of mRNA expression in different organs revealed differential effects of dietary lipids. In FO-fed mice, transforming growth factor beta1 (TGF beta1) expression was decreased in kidneys, but splenic tissues had higher expression of TGF beta mRNA. As TGF beta promotes programmed cell death (PCD), we studied the effects of CO and FO on PCD rates in lymphocytes. Both propidium iodide staining and DNA fragmentation were elevated in lymphocytes of FO-fed mice when compared to CO-fed mice of similar age. Also, increased PCD correlated closely with increased Fas gene expression. Thus, in addition to various other antiinflammatory effects, dietary FO appears to increase PCD and prevent accumulation of self reactive immune cells in lymphoid organs. Further studies are required to dissect the pro- and antiinflammatory mechanisms associated with dietary n-3 and n 6 lipids in modulating autoimmune disorders or malignancy during aging.

Dietary marine lipids suppress continuous expression of interleukin-1beta gene transcription

Lipids (USA), 1996, 31/3 SUPPL. (S23-S31)

n-3 Polyunsaturated fatty acids abundant in marine lipids suppress certain inflammatory and immune reactions, and dietary marine lipid supplements have antiinflammatory effects in experimental and human autoimmune disease. Previous work by other investigators demonstrated that dietary marine lipid supplements suppressed production of cytokines from stimulated human peripheral blood mononuclear cells ex vivo. The present study further documents the ability of n 3 fatty acids to inhibit cytokine formation, and in part defines the mechanism of the inhibition of production of interleukin- 1beta (IL-1beta) by dietary n-3 fatty acid. Female BALB/c mice were each fed a fat-free balanced diet to which was added either a refined fish oil (FO) preparation as a source of n-3 fatty acid, or beef tallow (BT), which consisted primarily of saturated and monoenoic fatty acids. After ingesting the experimental diets for periods ranging from 3 to 12 wk, spleen cell preparations were stimulated ex vivo with either lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate (PMA), and proIL-1beta mRNA (IL-1beta mRNA) was measured by northern analysis. Levels of IL-1beta mRNA in both LPS- and PMA- stimulated cells from BT-fed mice were elevated to a greater extent than in cells from FO-fed mice, at most concentrations of LPS and PMA. Stability of LPS-stimulated mRNA levels after actinomycin D was similar for BT and FO groups, indicating that lower levels of IL-1 mRNA with FO groups was related to suppressed IL-1 gene transcription and not due to accelerated transcript degradation. Nuclear run-on transcription assays revealed a more transient expression of the IL-1beta gene in LPS-stimulated spleen cells from FO-fed mice compared to cells from BT-fed mice. We conclude that dietary marine lipids reduce transient expression of the IL-1beta gene in stimulated splenic monocytic cells. Preliminary results from nuclear run-on transcription assays indicate that n-3 fatty acids may not change the initial rate of gene transcription but may promote more rapid shutting down of transcription of this gene after induction than do alternative lipids.

Decreased pro-inflammatory cytokines and increased antioxidant enzyme gene expression by omega-3 lipids in murine lupus nephritis

BIOCHEM. BIOPHYS. RES. COMMUN. (USA), 1994, 200/2 (893-898)

Enrichment of diet with omega-3 lipid rich-menhaden fish oil (FO) when fed ad libitum to autoimmune lupus-prone NZB/NZW F1 (B/W) female mice delayed the onset and slowed progression of renal disease while significantly extending life-span compared to omega-6 lipid rich-corn oil (CO)-fed mice. Northern blot analysis of kidneys from FO-fed mice revealed no detectable levels of IL-1beta, IL-6 and TNFalpha mRNA contrasted to levels that were easily detected in CO-fed mice. In contrast to the cytokines, FO-fed mice showed higher renal levels of the antioxidant enzymes-catalase, glutathione peroxidase (GSH-Px), superoxide dismutase (SOD)-mRNAs compared to CO-fed mice. The results suggest that dietary supplementation with FO, as compared to CO, inhibits the production of pro-inflammatory cytokines and ameliorates immune-complex-mediated kidney injury possibly by enhancing the ability of cells to dispose of harmful reactive oxygen intermediates.