Here are the abstracts to save people some work.
1: J Neurochem. 1980 Oct;35(4):1004-7.
Transient formation of superoxide radicals in polyunsaturated fatty acid-induced brain swelling.
Chan PH, Fishman RA.
The involvement of superoxide free radicals and lipid peroxidation in brain swelling induced by free fatty acids has been studied in brain slices and homogenates. The polyunsaturated fatty acids linoleic acid (18:2), linolenic acid (18:3), arachidonic acid (20:4), and docosahexaenoic acid (22:6) caused brain swelling concomitant with increases in superoxide and membrane lipid peroxidation. Palmitic acid (16:0) and oleic acid (18:1) had no such effect. Furthermore, superoxide formation was stimulated by NADPH and scavenged by the addition of exogenous superoxide dismutase in cortical slice homogenates. These in vitro data support the hypothesis that both superoxide radicals and lipid peroxidation are involved in the mechanism of polyunsaturated fatty acid-induced brain edema.
2: Brain Res. 1982 Sep 23;248(1):151-7.
Alterations of membrane integrity and cellular constituents by arachidonic acid in neuroblastoma and glioma cells.
Chan PH, Fishman RA.
Effects of arachidonic acid on cellular metabolism, cation content, lipid peroxidation, sodium pump activities and release of labeled arachidonic acid were studied in C-6 glioma cells and N18TG2 neuroblastoma cells. Arachidonic acid caused a significant increase in intracellular sodium levels concomitant with a decrease in intracellular potassium in both cell lines. Both (Na+ + K+)-ATPase and p-nitrophenyl phosphatase of glioma cells were inhibited by arachidonic acid whereas only the p-nitrophenyl phosphatase of neuroblastoma cell was inactivated. Low concentrations of arachidonic acid stimulated lactic acid release whereas high concentrations had an opposite effect. In addition, the lipid peroxide content of glioma cells was increased abruptly by 50 microM arachidonic acid whereas only a slight increase of malondialdehyde was observed in neuroblastoma cells. When the cultured cells of both cell lines were incubated with exogenous labeled arachidonic acid, 78-95% of the label was incorporated into membrane phospholipids. Only a very small fraction of prostaglandin E2 and prostaglandin F2 alpha was synthesized. Exogenous arachidonic acid and free radicals generated with xanthine-xanthine oxidase caused a significant release of endogenous labeled arachidonic acid from cellular membrane phospholipids. These data further support our hypothesis that the arachidonic acid and its oxygen radical metabolites induce pathological alterations in membrane permeability and cellular volume.
3: J Neurochem. 1982 Feb;38(2):525-31.
Phospholipid degradation and cellular edema induced by free radicals in brain cortical slices.
Chan PH, Yurko M, Fishman RA.
Cellular edema and increased lactate production were induced in rat brain cortical slices by xanthine oxidase and xanthine, in the presence of ferric dialdehyde, was increased 174%. Among the various subcellular fractions of brain cortex, xanthine oxidase-stimulated lipid peroxidation was highest in myelin, mitochondria, and synaptosomes, followed by microsomes and nuclei. Antioxidants, catalase, chlorpromazine, and butylated hydroxytoluene inhibited lipid peroxidation in both homogenates and synaptosomes, indicating H2O2 and radicals were involved. Further, several free fatty acids, especially oleic acid (18:1), arachidonic acid (20:4), and docosahexaenoic acid (22:6) were released from the phospholipid pool concomitant with the degradation of membrane phospholipids in xanthine oxidase-treated synaptosomes. These data suggest that lipases are activated by free radicals and lipid peroxides in the pathogenesis of cellular swelling.
4: J Neurosci Res. 1984;12(4):595-605.
Release of polyunsaturated fatty acids from phospholipids and alteration of brain membrane integrity by oxygen-derived free radicals.
Chan PH, Fishman RA, Schmidley JW, Chen SF.
We studied the effects of oxygen-derived free radicals on the ultrastructure of brain cortical slices and the release of fatty acids from phospholipids of crude synaptosomes. Xanthine oxidase, hypoxanthine, and ADP-Fe3+, a free-radical-generating system, caused swelling of cellular processes and mitochondria. The oxygen-derived free radicals also caused the rapid release and accumulation of endogenous polyunsaturated fatty acids (PUFA) from membrane phospholipids as determined by high-performance liquid chromatography (HPLC). Furthermore, [3H]-arachidonic acid was also rapidly released from prelabeled phospholipids concomitant with a decrease in radioactivity in various phospholipid fractions. The radioactivities of neutral lipids including diacylglycerols were unchanged by free radicals. These data indicate that the activation of phospholipase A2 and the release of PUFA may have overt effect on membrane integrity and the subsequent development of cellular injury and brain edema.
5: J Neurochem. 1988 Apr;50(4):1185-93.
Induction of intracellular superoxide radical formation by arachidonic acid and by polyunsaturated fatty acids in primary astrocytic cultures.
Chan PH, Chen SF, Yu AC.
Department of Neurology, University of California, School of Medicine, San Francisco 94143.
The effects of arachidonic acid and other polyunsaturated fatty acids (PUFAs) on both oxidative and metabolic perturbation were studied in primary cultures of rat cerebral cortical astrocytes. In the presence of 0.1 mM arachidonic acid, the rate of the reduction of nitroblue tetrazolium (NBT) to nitroblue formazan (NBF) was stimulated from 0.65 +/- 0.10 to 1.43 +/- 0.15 and from 0.092 +/- 0.006 to 0.162 +/- 0.009 nmol/min/mg protein in intact and broken cell preparations, respectively. The rate of superoxide radical formation, as measured by the superoxide dismutase (SOD)-inhibitable NBT reduction was 0.042 nmol/mg protein in broken cells and was negligible in intact cells. The latter is due to the impermeability of SOD into the intact cell preparation. NBF formation in intact astrocytes stimulated by arachidonic acid was both time- and dose-dependent. Other PUFAs, including linoleic acid, linolenic acid, and docosahexaenoic acid, were also effective in stimulating NBF formation in astrocytes, whereas saturated palmitic acid and monounsaturated oleic acid were ineffective. Similar effects of these PUFAs were observed in malondialdehyde formation in cells and lactic acid accumulation in incubation medium. These data indicate that both membrane integrity and cellular metabolism were perturbed by arachidonic acid and by other PUFAs. The sites of superoxide radical formation appeared to be intracellular and may be associated with membrane phospholipid domains, because liposome-entrapped SOD, which was taken up by intact astrocytes, reduced the level of superoxide radicals and lactic acid content, whereas free SOD was not effective.
6: J Neurosci Res. 1988 Aug;20(4):451-6.
Role of arachidonic acid and other free fatty acids in mitochondrial dysfunction in brain ischemia.
Hillered L, Chan PH.
Department of Neurology, School of Medicine, University of California, San Francisco 94143.
The aim of the present investigation was to evaluate the possible role of arachidonic acid and other free fatty acids in ischemia-induced mitochondrial dysfunction. Respiratory activities were measured in mitochondria isolated from rat brains subjected to 15-30 min of decapitation ischemia. Addition of bovine serum albumin (BSA) to the mitochondria, isolated in BSA-free media, abolished an ischemia-induced increase in substrate-stimulated (state 4) respiration but only partly reversed a marked inhibition of substrate-, phosphate-, and ADP-stimulated (state 3) respiration caused by the ischemia. Individual free fatty acids were measured in aliquots of the same mitochondrial preparations before and after treatment with BSA. There was a significant increase in arachidonic (20:4), stearic (18:0), palmitic (16:0), and docosahexaenoic (22:6) acid during ischemia. BSA treatment removed all 20:4 and reduced the amount of 18:0 and 16:0, but had no significant effect on 22:6. The main conclusions were 1) that 20:4, 18:0, and 16.0 were responsible for the partial uncoupling (increase in state 4 respiration) of mitochondrial respiration during ischemia, 2) that the inhibition of state 3 respiration caused by ischemia could only partly be attributed to an effect of FFAs, and 3) that the ischemia-induced mitochondrial dysfunction was caused by a combination of factors including 20:4.
7: J Neurosci Res. 1989 Oct;24(2):247-50.
Brain mitochondrial swelling induced by arachidonic acid and other long chain free fatty acids.
Hillered L, Chan PH.
Department of Neurology, University of California, School of Medicine, San Francisco 94143.
Polyunsaturated fatty acids (PUFAs), arachidonic acid in particular, are well known, potent inducers of edema in the brain, while monounsaturated and saturated long chain fatty acids do not possess this quality. This investigation has compared the ability of some free fatty acids (FFAs), known to be released during cerebral ischemia, to induce brain mitochondrial swelling in vitro. The PUFAs tested, especially arachidonic acid (20:4), were more potent in causing swelling than saturated or monounsaturated ones, as measured by the decrease in light absorbance of the mitochondrial suspension. This finding is in line with the unique potency of 20:4 to induce brain edema. Incubation of brain mitochondria with 20:4 for 20 min caused a dose-dependent swelling. ATP-MgCl2 both prevented and reversed this swelling, while binding of the 20:4 by the addition of bovine serum albumin could only prevent but not reverse the swelling. The contraction of the swollen mitochondria appeared to be mediated by a mechanism dependent upon high-energy phosphates, potentiated by MgCl2. The concentration of 20:4 required to induce swelling was about 20 times higher than the concentration required to induce inhibition of mitochondrial respiratory function (L Hillered and P H Chan: J Neurosci Res 19:94-100, 1988a). Moreover, reversal of the swelling occurred without recovery of respiratory function. These results suggest that swelling is a phenomenon of minor importance as an indicator of brain mitochondrial dysfunction, at least when induced by 20:4 in vitro.
8: J Physiol. 1994 Feb 15;475(1):83-93.
Facilitatory effect of docosahexaenoic acid on N-methyl-D-aspartate response in pyramidal neurones of rat cerebral cortex.
Nishikawa M, Kimura S, Akaike N.
Department of Neurophysiology, Tohoku University School of Medicine, Sendai, Japan.
- The effect of docosahexaenoic acid (DHA) on N-methyl-D-aspartic acid (NMDA) responses in the presence of glycine was investigated in pyramidal neurons acutely dissociated from rat cerebral cortex in whole-cell and single channel configurations. 2. DHA potentiated the NMDA-induced response but reduced the non-NMDA (kainate-induced) response in a concentration-dependent manner at a holding potential of -60 mV under voltage-clamp conditions. 3. Arachidonic acid (AA) also potentiated the NMDA-induced response in a manner similar to DHA. Oleic acid caused a slight potentiation. However, other polyunsaturated and saturated fatty acids had no such effects. 4. The facilitatory action of DHA on the NMDA-induced response was not affected by adding inhibitors of cyclo-oxygenase, lipoxygenase or phospholipase A2, suggesting that DHA may exert its facilitatory effect directly on the NMDA receptor. 5. The facilitatory action of DHA was observed in the presence of a saturating dose of NMDA. Moreover, a detailed analysis of the NMDA receptor-operated single channel currents revealed that, in the presence of DHA, the open probability of the channel increased without changing the conductance, indicating that DHA may act by binding directly to a novel site on the NMDA receptor or by altering the lipid environment of the NMDA receptor and thereby potentiating the response to NMDA. 6. The results are discussed in terms of the possibility that DHA may play an important role in the genesis of long-term potentiation, at least that involving the activation of NMDA receptors.
Inhibition of bioenergetics alters intracellular calcium, membrane composition, and fluidity in a neuronal cell line
9: Free Radic Biol Med. 2000 Oct 15;29(8):714-20.
Acrolein, a product of lipid peroxidation, inhibits glucose and glutamate uptake in primary neuronal cultures.
Lovell MA, Xie C, Markesbery WR.
Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536-0230, USA.
Oxidative stress has been implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease (AD). Increased lipid peroxidation, decreased levels of polyunsaturated fatty acids, and increased levels of 4-hydroxynonenal (HNE), F(2)-isoprostanes, and F(4)-neuroprostanes are present in the brain in patients with AD. Acrolein, an alpha,beta-unsaturated aldehydic product of lipid peroxidation has been demonstrated to be approximately 100 times more reactive than HNE and is present in neurofibrillary tangles in the brain in AD. We recently demonstrated statistically significant elevated concentrations of extractable acrolein in the hippocampus/parahippocampal gyrus and amygdala in AD compared with age-matched control subjects. Concentrations of acrolein were two to five times those of HNE in the same samples. Treatment of hippocampal cultures with acrolein led to a time- and concentration-dependent decrease in cell survival as well as a concentration-dependent increase in intracellular calcium. In cortical neuron cultures, we now report that acrolein causes a concentration-dependent impairment of glutamate uptake and glucose transport in cortical neuron cultures. Treatment of cortical astrocyte cultures with acrolein led to the same pattern of impairment of glutamate uptake as observed in cortical neuron cultures. Collectively, these data demonstrate neurotoxicity mechanisms of arolein that might be important in the pathogenesis of neuron degeneration in AD.
10: Lipids. 1996 Aug;31(8):829-37.
Effect of dietary n-9 eicosatrienoic acid on the fatty acid composition of plasma lipid fractions and tissue phospholipids.
Cleland LG, Neumann MA, Gibson RA, Hamazaki T, Akimoto K, James MJ.
Rheumatology Unit, Royal Adelaide Hospital, Australia.
n-9 Eicosatrienoic acid (ETrA), also known as Mead acid, is a minor fatty acid in essential fatty acid (EFA)-sufficient healthy subjects but is found at increased levels in EFA deficiency. This study examined the influence of dietary ETrA from a biological source on plasma and tissue ETrA. A synthetic fat-free diet was prepared to which was added Mut 48 oil which contains 19% ETrA (wt%) as well as other n-9 fatty acids. Blends of vegetable oils were used to achieve overall diets with 5% fat (wt%) and varying amounts of ETrA at two different dietary levels of linoleic acid (LA), approximately 4.4 and 19% of total fatty acids. These diets were fed to 5-week-old Dark Agouti rats for four weeks. Plasma lipid fractions and liver, spleen, and peritoneal exudate (PE) cells were analyzed for fatty acid composition. ETrA was present at up to 20% total fatty acids in plasma triglyceride, cholesterol ester, and phospholipid fractions. ETrA also accumulated to substantial levels in phospholipids of liver and spleen (up to 15% of total fatty acids) and PE cells (up to 11%). ETrA was found in plasma and tissue phospholipids in proportion to the amount of ETrA present in the diet. The incorporation was reduced in diets with higher LA content compared to diets containing similar amounts of ETrA but lower LA. All rats remained apparently healthy, and histological survey of major organs revealed no abnormality. While the long-term implications for health of ingestion of diets rich in ETrA remain to be established, rats appear to tolerate high levels of dietary ETrA without adverse effects. Dietary enrichment with ETrA warrants further investigation for possible beneficial effects in models of inflammation and autoimmunity, as well as in other conditions in which mediators derived from n-6 fatty acids can affect homeostasis adversely.
11: Clin Exp Allergy. 2004 Feb;34(2):194-200.
Maternal breast milk long-chain n-3 fatty acids are associated with increased risk of atopy in breastfed infants.
Stoney RM, Woods RK, Hosking CS, Hill DJ, Abramson MJ, Thien FC.
Department of Nutrition, The Alfred Hospital, Melbourne, Victoria, Australia.
BACKGROUND: Australia has one of the highest prevalence rates internationally of allergic conditions, such as asthma and eczema. Atopy is one hallmark for the development of allergic disease and predisposes to allergic inflammation in the target organs. omega-3 (n-3) fatty acids (FAs) are thought to act as precursors to the formation of less active inflammatory mediators, with the potential to reduce inflammation. OBJECTIVE: To investigate whether increased n-3 FA levels in maternal breast milk are associated with a lower risk of developing atopy in infancy. METHODS: Subjects were part of the prospective Melbourne atopy cohort study, which involved 620 children born into families where at least one first-degree relative had an atopic disease. Some 224 women (mean age 31.4+/-4.2 (SD) years, with 73.2% (n=164) having self-reported atopy) provided either a colostrum (n=194) or 3-month expressed breast milk (EBM) sample (n=118). Maternal colostrum and 3-month EBM samples were analysed for FA content by gas chromatography. Skin prick tests (SPTs) to six common allergens were performed on infants at 6, 12 and 24 months of age and on mothers who agreed at study entry. RESULTS: For infants sensitized to foods at 6 months (n=29), the total n-3 FA level in the colostrum was significantly higher (P=0.004) as were levels of individual long-chain n-3 FAs, docosoapentaenoic acid (DPA, C22:5, P=0.001) and docosahexaenoic acid (DHA, C22:6, P=0.002) than in non-sensitized infants. Infants with aero-allergen sensitization at 24 months (n=30) had higher levels of the n-3 FA, DPA (P=0.002) and DHA (P=0.007), and similarly higher total n-3 FA (P=0.009) in maternal colostrum than those infants who were not sensitized. CONCLUSION: Higher n-3 FA levels in the colostrum do not appear to confer protection against, but may be a risk factor for, the eventual development of atopy in high-risk breastfed infants.
12: Am J Psychiatry. 2004 Mar;161(3):567-9.
Am J Psychiatry. 2005 Feb;162(2):402; author reply 402-3.
Is low dietary intake of omega-3 fatty acids associated with depression?
Hakkarainen R, Partonen T, Haukka J, Virtamo J, Albanes D, Lonnqvist J.
Department of Mental Health and Alcohol Research, National Public Health Institute, Helsinki, Finland. firstname.lastname@example.org
OBJECTIVE: This study examined the association between the dietary intake of omega-3 fatty acids and low mood, major depression, and suicide. METHOD: A total of 29,133 men ages 50 to 69 years participated in a population-based trial in Finland. The intake of fatty acids and fish consumption were calculated from a diet history questionnaire. Self-reported depressed mood was recorded three times annually, data on hospital treatments due to a major depressive disorder were derived from the National Hospital Discharge Register, and suicides were identified from death certificates. RESULTS: There were no associations between the dietary intake of omega-3 fatty acids or fish consumption and depressed mood, major depressive episodes, or suicide. CONCLUSIONS: Dietary intake of omega-3 fatty acids showed no association with low mood level.
And a few others...
13: Eur J Clin Nutr. 2003 Jun;57(6):793-800.
Increased lipid peroxidation during long-term intervention with high doses of n-3 fatty acids (PUFAs) following an acute myocardial infarction.
Grundt H, Nilsen DW, Mansoor MA, Nordoy A.
Department of Clinical Chemistry, Central Hospital in Rogaland, POB 8100, 4068 Stavanger, Norway. email@example.com
OBJECTIVE: To assess the oxidative burden of a highly concentrated compound of n-3 PUFAs as compared to corn oil by measuring thiobarbituric acid-malondialdehyde complex (TBA-MDA) by HPLC. We also studied the influence on TBA-MDA of statins combined with n-3 PUFAs or corn oil. DESIGN: A prospective, randomised, double-blind, controlled study. SETTING: One hospital centre in Stavanger, Norway. SUBJECTS: A total of 300 subjects with an acute myocardial infarction (MI). INTERVENTIONS: Gelatine capsules, containing 850-882 mg EPA and DHA as concentrated ethylesters, or 1 g of corn oil, were ingested in a dose of two capsules twice a day for at least 1 y. Alpha-tocopherol (4 mg) was added to all capsules to protect the PUFAs against oxidation. RESULTS: After 1 y TBA-MDA increased modestly in the n-3 PUFA group (n=125), as compared to the corn oil group (n=130), P=0.027. Multiple linear regression analyses of fatty acids in serum total phospholipids (n=56) on TBA-MDA measured after 12 months intervention, showed no dependency. Performing best subsets regression, serum phospholipid concentration of arachidonic acid (20:4 n-6 PUFA) was identified as a predictor of TBA-MDA at 12 months follow-up, P=0.004.We found no impact of statins on TBA-MDA. CONCLUSION: TBA-MDA increased modestly after long-term intervention with n-3 PUFAs compared to corn oil post-MI, suggesting biological changes induced by n-3 PUFAs, rather than simply reflecting their concentration differences. The peroxidative potential of n-3 PUFAs was not modified by statin treatment. SPONSORSHIP:: Pharmacia A/S and Pronova A/S, Norway.
14: Arterioscler Thromb Vasc Biol. 2000 Mar;20(3):708-14.
Oxidized cholesterol in the diet accelerates the development of atherosclerosis in LDL receptor- and apolipoprotein E-deficient mice.
Staprans I, Pan XM, Rapp JH, Grunfeld C, Feingold KR.
Department of Veterans Affairs Medical Center, University of California, San Francisco 94121, USA. firstname.lastname@example.org
The aim of the current study was to determine whether oxidized cholesterol in the diet accelerates atherosclerosis in low density lipoprotein receptor- (LDLR) and apolipoprotein E- (apo E) deficient mice. Mice were fed either a control diet or a diet containing oxidized cholesterol. For LDLR-deficient mice, the control diet consisted of regular mouse chow to which 1.0% cholesterol was added. The oxidized diet was identical to the control diet except that 5% of the added cholesterol was oxidized. In apo E-deficient mice, the control diet contained 0.15% cholesterol, whereas in the oxidized diet, 5% of the added cholesterol was oxidized. LDLR-deficient and apo E-deficient mice were fed the experimental diets for 7 and 4 months, respectively. In mice fed the oxidized-cholesterol diets, the levels of oxidized cholesterol in sera were increased. At the end of the experiment, aortas were removed and atherosclerosis was assessed. We found that in LDLR-deficient mice, feeding of an oxidized-cholesterol diet resulted in a 32% increase in fatty streak lesions (15.93+/-1.59% versus 21.00+/-1.38%, P<0.03). Similarly, in apo E-deficient mice, feeding of an oxidized-cholesterol diet increased fatty streak lesions by 38% (15.01+/-0.92% versus 20. 70+/-0.86%, P<0.001). The results of the current study thus demonstrate that oxidized cholesterol in the diet accelerates fatty streak lesion formation in both LDLR- and apo E-deficient mice.
15: Atherosclerosis. 2001 Mar;155(1):9-18.
Enhanced level of n-3 fatty acid in membrane phospholipids induces lipid peroxidation in rats fed dietary docosahexaenoic acid oil.
Song JH, Miyazawa T.
Department of Applied Biological Chemistry, Faculty of Agriculture, Tohoku University, 981-8555, Sendai, Japan.
The effect of dietary docosahexaenoic acid (DHA, 22:6n-3) oil with different lipid types on lipid peroxidation was studied in rats. Each group of male Sprague-Dawley rats was pair fed 15% (w/w) of either DHA-triglycerides (DHA-TG), DHA-ethyl esters (DHA-EE) or DHA-phospholipids (DHA-PL) for up to 3 weeks. The palm oil (supplemented with 20% soybean oil) diet without DHA was fed as the control. Dietary DHA oils lowered plasma triglyceride concentrations in rats fed DHA-TG (by 30%), DHA-EE (by 45%) and DHA-PL (by 27%), compared to control. The incorporation of dietary DHA into plasma and liver phospholipids was more pronounced in the DHA-TG and DHA-EE group than in the DHA-PL group. However, DHA oil intake negatively influenced lipid peroxidation in both plasma and liver. Phospholipid peroxidation in plasma and liver was significantly higher than control in rats fed DHA-TG or DHA-EE, but not DHA-PL. These results are consistent with increased thiobarbituric acid reactive substances (TBARS) and decreased alpha-tocopherol levels in plasma and liver. In addition, liver microsomes from rats of each group were exposed to a mixture of chelated iron (Fe(3+)/ADP) and NADPH to determine the rate of peroxidative damage. During NADPH-dependent peroxidation of microsomes, the accumulation of phospholipid hydroperoxides, as well as TBARS, were elevated and alpha-tocopherol levels were significantly exhausted in DHA-TG and DHA-EE groups. During microsomal lipid peroxidation, there was a greater loss of n-3 fatty acids (mainly DHA) than of n-6 fatty acids, including arachidonic acid (20:4n-6). These results indicate that polyunsaturation of n-3 fatty acids is the most important target for lipid peroxidation. This suggests that the ingestion of large amounts of DHA oil enhances lipid peroxidation in the target membranes where greater amounts of n-3 fatty acids are incorporated, thereby increasing the peroxidizability and possibly accelerating the atherosclerotic process.
16: Food Chem Toxicol. 1998 Aug;36(8):663-72.
The association of increasing dietary concentrations of fish oil with hepatotoxic effects and a higher degree of aorta atherosclerosis in the ad lib.-fed rabbit.
Ritskes-Hoitinga J, Verschuren PM, Meijer GW, Wiersma A, van de Kooij AJ, Timmer WG, Blonk CG, Weststrate JA.
Unilever Nutrition Centre, Unilever Research Laboratory, Vlaardingen, The Netherlands.
The long-term effects of consumption of marine long-chain n-3 polyunsaturated fatty acids (PUFA) on atherosclerosis in the rabbit were examined. Female Dutch rabbits were fed purified diets, containing 40 energy% total fat, for a period of 2.5 years. To study the dose response relationship between fish oil intake and atherosclerosis, four diets were formulated with fish oil levels being 0, 1, 10 and 20 energy%. A fifth and sixth group were fed an alpha-linolenic acid-(C18:3, n-3) and linoleic acid-(C18:2, n-6) rich diet, respectively. Every 6 weeks, blood samples were taken for determination of clinical chemical parameters, triacylglycerol and total cholesterol levels. Feeding 10 and 20 energy% fish oil containing diets, resulted in an increase of liver enzymes (AST, ALT and ALP). Histological evaluation of the liver also revealed adverse effects of fish oil containing diets. Triacylglycerol blood levels were similar in all groups, and remained constant throughout the study. Total cholesterol levels in blood was significantly lower in the animals fed a linoleic acid-rich diet, as compared with the other five groups. An n-3 long-chain PUFA concentration dependent increase in aorta plaque surface area was observed in the fish oil groups. A significant positive relationship was found between the group mean score for severity of liver pathology and the aorta plaque surface area. These results indicate that the long-chain n-3 polyunsaturated fatty acids in fish oil may be hepatotoxic to the herbivorous rabbit, which may interfere with the outcome of atherosclerosis studies. This finding necessitates the exclusion of liver pathology in experimental studies on atherosclerosis in animal models.
17: Int J Circumpolar Health. 2001 Apr;60(2):143-9.
Cod liver oil consumption, smoking, and coronary heart disease mortality: three counties, Norway.
Egeland GM, Meyer HE, Selmer R, Tverdal A, Vollset SE.
National Health Screening Service, Research Department, P.O. Box 8155, 0033 Oslo, Norway. email@example.com
It has been hypothesized that omega-3 fatty acid consumption may lessen the adverse effect of smoking on coronary heart disease (CHD) risk. Thus, we explored whether cod liver oil consumption was protective of coronary heart disease in a cohort of men and women participating in a cardiovascular disease screening in Norway. The study population was aged 35-54 at the time of the baseline screening conducted by the National Health Screening Service of Norway in 1977-1983. Of 56,718 age-eligible men and women, 52,138 participated, of whom 42,612 (82%) completed a dietary questionnaire. Cod liver oil use was reported by 12.5%. At baseline, cod liver oil users had lower triglycerides, adjusting for age, body mass index, time since last meal and income (p < or = .05). As of December 1992, 639 and 118 CHD deaths were observed among the men and women, respectively. Overall, we observed no effect of cod liver oil consumption reported at baseline and CHD mortality in Cox Proportional Hazards analyses [Hazard Ratio (HR) = 1.0 (0.8-1.3)]. In analyses, stratified by smoking status, never smokers and current smokers showed non-significant beneficial associations between cod liver oil use and CHD mortality (HR = 0.7, 95% CI = 0.4-1.5; and HR = 0.8, 95% CI = 0.6-1.2, respectively). However, among former smokers a non-significant excess risk of CHD mortality was associated with cod liver oil use (HR = 1.6, 95% CI = 0.9-2.6). Smokers, regardless of their cod liver oil use were at a substantially higher risk for CHD mortality relative to non-smokers. Omega-3 fatty acid supplementation, as practiced in this cohort, provided no significant benefits to CHD risk among study participants.
18: Lipids. 1997 Jul;32(7):745-51.
Unusual effects of some vegetable oils on the survival time of stroke-prone spontaneously hypertensive rats.
Huang MZ, Watanabe S, Kobayashi T, Nagatsu A, Sakakibara J, Okuyama H.
Faculty of Pharmaceutical Sciences, Nagoya City University, Japan.
Preliminary experiments have shown that a diet containing 10% rapeseed oil (low-erucic acid) markedly shortens the survival time of stroke-prone spontaneously hypertensive (SHRSP) rats under 1% NaCl loading as compared with diets containing perilla oil or soybean oil. High-oleate safflower oil and high-oleate sunflower oil were found to have survival time-shortening activities comparable to that of rapeseed oil; olive oil had slightly less activity. A mixture was made of soybean oil, perilla oil, and triolein partially purified from high-oleate sunflower oil to adjust the fatty acid composition to that of rapeseed oil. The survival time of this triolein/mixed oil group was between those of the rapeseed oil and soybean oil groups. When 1% NaCl was replaced with tap water, the survival time was prolonged by approximately 80%. Under these conditions, the rapeseed oil and evening primrose oil shortened the survival time by approximately 40% as compared with n-3 fatty acid-rich perilla and fish oil; lard, soybean oil, and safflower oil with relatively high n-6/n-3 ratios shortened the survival time by roughly 10%. The observed unusual survival time-shortening activities of some vegetable oils (rapeseed, high-oleate safflower, high-oleate sunflower, olive, and evening primrose oil) may not be due to their unique fatty acid compositions, but these results suggest that these vegetable oils contain factor(s) which are detrimental to SHRSP rats.
19: Lipids. 1998 Jul;33(7):655-61.
Free fatty acid fractions from some vegetable oils exhibit reduced survival time-shortening activity in stroke-prone spontaneously hypertensive rats.
Miyazaki M, Huang MZ, Takemura N, Watanabe S, Okuyama H.
Department of Biological Chemistry, Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan.
Previously, we demonstrated that several vegetable oils that included low-erucic rapeseed oil markedly shortened the survival time (by approximately 40%) of stroke-prone spontaneously hypertensive (SHRSP) rats as compared with perilla oil, soybean oil, and fish oil. We considered that a factor other than fatty acids is toxic to SHRSP rats, because the survival time-shortening activity could not be accounted for by the fatty acid compositions of these oils. In fact, a free fatty acid (FFA) fraction derived from lipase-treated rapeseed oil was found to be essentially devoid of such activity. A high-oleate safflower oil/safflower oil/perilla oil mixture exhibited a survival time-shortening activity comparable to that of rapeseed oil, but the activity of this mixed oil was also reduced by lipase treatment. A partially hydrogenated soybean oil shortened the survival time by approximately 40%, but a FFA fraction derived from lipase-treated partially hydrogenated soybean oil shortened it by 13% compared with soybean oil. Fatty acid compositions of the rapeseed oil and a FFA fraction derived from lipase-treated rapeseed oil were similar, but those of hepatic phospholipids of rats fed the oil and FFA were slightly but significantly different. These results support the interpretation that the survival time-shortening activity exhibited by some vegetable oils is due to minor components other than fatty acids, and that an active component(s) were produced in or contaminated soybean oil during the partial hydrogenation processes.
20: Br J Nutr. 2003 Oct;90(4):777-86.
Fish-oil supplementation reduces stimulation of plasma glucose fluxes during exercise in untrained males.
Delarue J, Labarthe F, Cohen R.
Laboratoire Regional de Nutrition Humaine & EA-948, Medecine 4-Nutrition, CHU Cavale Blanche, F-29200-Brest, France. firstname.lastname@example.org
The present study examined the effects of a 3-week fish-oil supplementation (6 g/d) on the rate of plasma glucose disappearance (Rd glucose), hepatic glucose production (HGP), carbohydrate oxidation and lipid oxidation during exercise. Six untrained males (23+/-1 years; 67.6+/-2.7 kg) performed two 90 min cycling exercise sessions at 60 % of maximal O2 output separated by 20 d. During the 20 d before the first test, they ingested 6 g olive oil/d, then 6 g fish oil/d during the 20 d before the second test. Plasma glucose fluxes and lipolysis were traced using 6,6-[(2)H2]glucose and 1,1,2,3,3-[(2)H5]glycerol respectively. Substrates oxidation was obtained from indirect calorimetry. At rest HGP and the Rd glucose were similar after olive oil and fish oil (1.83 (SE 0.05) v. 1.67 (SE 0.11) mg/kg per min). During exercise, fish oil reduced the stimulation of both the Rd glucose (5.06 (SE 0.23) v. 6.37 (SE 0.12) mg/kg per min; P<0.05) and HGP (4.88 (SE 0.24) v. 5.91 (SE 0.21) mg/kg per min; P<0.05). Fish oil also reduced glucose metabolic clearance rate (6.93 (SE 0.29) v. 8.30 (SE 0.57) ml/min). Carbohydrate oxidation tended to be less stimulated by exercise after fish oil than after olive oil (12.09 (SE 0.60) v. 13.86 (se 1.11) mg/kg per min; NS). Lipid oxidation tended to be more stimulated by exercise after fish oil (7.34 (SE 0.45) v. 6.85 (SE 0.17) mg/kg per min; NS). Glycaemia, lactataemia, insulinaemia and glucagonaemia were similarly affected by exercise after fish oil and olive oil. Lipolysis at rest was similar after fish oil and olive oil (2.92 (SE 0.42) v. 2.94 (SE 0.28) micromol/kg per min) and similarly stimulated by exercise (6.42 (SE 0.75) v. 6.77 (SE 0.72) micromol/kg per min). It is concluded that fish oil reduced the Rd glucose by 26 % by reducing glucose metabolic clearance rate, possibly by facilitating fat oxidation, and reduced HGP by 21%, possibly by a feedback mechanism.
21: Endocrinology. 2003 Sep;144(9):3958-68.
Diabetogenic impact of long-chain omega-3 fatty acids on pancreatic beta-cell function and the regulation of endogenous glucose production.
Holness MJ, Greenwood GK, Smith ND, Sugden MC.
Department of Diabetes and Metabolic Medicine, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London E1 4NS, United Kingdom.
In healthy individuals, peripheral insulin resistance evoked by dietary saturated lipid can be accompanied by increased insulin secretion such that glucose tolerance is maintained. Substitution of long-chain omega-3 fatty acids for a small percentage of dietary saturated fat prevents insulin resistance in response to high-saturated fat feeding. We substituted a small amount (7%) of dietary lipid with long-chain omega-3 fatty acids during 4 wk of high-saturated fat feeding to investigate the relationship between amelioration of insulin resistance and glucose-stimulated insulin secretion (GSIS). We demonstrate that, despite dietary delivery of saturated fat throughout, this manipulation prevents high-saturated fat feeding-induced insulin resistance with respect to peripheral glucose disposal and reverses insulin hypersecretion in response to glucose in vivo. Effects of long-chain omega-3 fatty acid enrichment to lower GSIS were also observed in perifused islets suggesting a direct effect on islet function. However, long-chain omega-3 fatty acid enrichment led to hepatic insulin resistance with respect to suppression of glucose output and impaired glucose tolerance in vivo. Our data demonstrate that the insulin response to glucose is suppressed to a greater extent than whole-body insulin sensitivity is enhanced by enrichment of a high-saturated fat diet with long-chain omega-3 fatty acids. Additionally, reduced GSIS despite glucose intolerance suggests that either long-chain omega-3 fatty acids directly impair the beta-cell response to saturated fat such that insulin secretion cannot be augmented to normalize glucose tolerance or beta-cell compensatory hypersecretion represents a response to insulin resistance at the level of peripheral glucose disposal but not endogenous glucose production.