Dietary saturated fatty acids and brain function

The degree to which fatty acids modulate brain function beyond periods of rapid brain growth is poorly understood. Nevertheless, recent evidence suggests that dietary fatty acid composition influences numerous behaviors including body temperature regulation, pain sensitivity, feeding behavior including macronutrient selection, and cognitive performance. Importantly, alterations are observed in the absence of essential fatty acid (EFA) deficiency, beyond periods of rapid brain development, and at levels similar to those consumed by the North American population. Data suggest that the content of saturated fatty acids (SFAs), and not that of the EFAs, may be the important component of dietary fat mediating macronutrient selection and cognition under these experimental conditions. Yet, a direct role of SFAs in modulating brain functions has not been elucidated. A discussion of potential mechanisms which may directly involve the central nervous system, or may indirectly influence central processes via peripheral pathway(s) is presented.     

Partial replacement of saturated fatty acids with almonds or walnuts lowers total plasma cholesterol and low-density-lipoprotein cholesterol

Sixteen normolipidemic male volunteers aged 41 +/- 9 y (mean +/- SD) consumed a diet providing 36% of energy as fat (92 g fat/d) for 9 wk. A daily supplement of nuts (providing half of the total fat intake) was provided against a common background diet. In the first 3-wk period the background diet was supplemented with raw peanuts (50 g/d), coconut cubes (40 g/d), and a coconut confectionary bar (50 g/d), designed to provide 47 g fat with a ratio of polyunsaturated to monounsaturated to saturated fatty acids (P:M:S) to match the Australian diet (reference diet). During the following 3 wk the background diet was supplemented with monounsaturated fatty acid-rich raw almonds (84 g/d), equivalent to 46 g fat, and during the final 3-wk period the background diet was supplemented with polyunsaturated fatty acid-rich walnuts (68 g/d), equivalent to 46 g fat. Compared with the reference diet there were significant reductions in total and LDL cholesterol, 7% and 10%, respectively, after supplementation with almonds, and 5% and 9%, respectively, after supplementation with walnuts.     

Plasma lipoprotein (a) levels in men and women consuming diets enriched in saturated, cis-, or trans-monounsaturated fatty acids

Studies that have shown adverse effects of trans-unsaturated fatty acids on plasma lipoprotein (a) [Lp(a)] levels have used levels of trans-fatty acid that are higher than those in the average U.S. diet. This study was conducted to clarify the effects on Lp(a) of trans-fatty acids levels commonly found in U.S. diets. Lp(a) levels were measured in a double-blind study of 29 men and 29 women who ate 4 controlled diets in random order for 6 weeks each. Fatty acids represented 39% to 40% of energy. The diets were: (1) Oleic (16.7% of energy as oleic acid); (2) Moderate trans (3.8% of energy as trans-monoenes, approximately the trans content of the U.S. diet); (3) High trans (6.6% of energy as trans-monoenes); (4) Saturated (16.2% of energy as lauric plus myristic plus palmitic acids). The Saturated diet lowered Lp(a) levels significantly (by 8% to 11%). Compared to the Oleic diet, the trans diets had no adverse effect on Lp(a) levels when all subjects were considered collectively. A subset with initially high levels of Lp(a) (> or = 30 mg/dL), however, responded to the High trans diet with a slight (5%) increase in Lp(a) levels relative to the Oleic and Moderate trans diets. Thus, in amounts commonly found in the typical U.S. diet, saturated fatty acids consistently decrease Lp(a) concentrations. The adverse effects of replacing cis- with trans-fatty acids are only suggestive and are restricted to high trans intakes in subjects with high Lp(a) levels.     

Dietary fatty acids and blood coagulation

Factor VII coagulant activity (VIIc) is a risk factor for coronary heart disease (CHD). Plasma VIIc is positively associated with dietary fat intake, suggesting that fat-rich diets are accompanied by a hypercoagulable state. Reduction in total fat consumption is followed by a decrease in VIIc within 24 h. In adults taking diets rich in long-chain saturated fatty acids, a postprandial increase in VIIc occurs after a fatty meal irrespective of its fat composition. This effect has dose-response characteristics, persists for several hours, and is due to activation of factor VII. There is no acute effect of dietary fat on factor VII antigen (VIIag) concentration, but VIIag is positively related to dietary fat intake. More studies are needed on the effects of dietary fat composition on fasting and postprandial factor VII. Dietary fat appears to influence both the atherosclerotic and thrombogenic components of CHD.     

Reducing saturated fat intake is associated with increased levels of LDL receptors on mononuclear cells in healthy men and women

1. Previous studies in our laboratory have shown that the synthetic xanthine analogue denbufylline, a selective type 4 phosphodiesterase (PDE-4) inhibitor, is a potent activator of the hypothalamo-pituitary-adrenal (HPA) axis when given orally or intraperitoneally (i.p.) to adult male rats. This paper describes the results of experiments in which well established in vivo and in vitro methods were used to compare the effects of denbufylline on HPA function with those of two other selective PDE-4 inhibitors, rolipram and BRL 61063 (1,3-dicyclopropylmethyl-8-amino-xanthine). For comparison, parallel measurements of the immunoreactive- (ir-) luteinising hormone (LH) were made where appropriate. 2. When injected intraperitoneally, rolipram (40 and 200 micrograms kg-1, P < 0.005), denbufylline (0.07-0.6 microgram kg-1, P < 0.05) and BRL 61063 (30 micrograms kg-1, P < 0.005) each produced marked rises in the serum ir-corticosterone concentrations. However, lower doses of rolipram (1.6 and 8 micrograms kg-1) and BRL 61063 (0.25-6 micrograms kg-1) were without effect (P > 0.05). By contrast, intracerebroventricular (i.c.v.) injection of rolipram (8 ng-1 micrograms kg-1) or denbufylline (50 ng-1 microgram kg-1) failed to influence the serum ir-corticosterone concentration. BRL 61063 (8-120 ng kg-1, i.c.v.) was also ineffective in this regard although at a higher dose (1 microgram kg-1, i.c.v.) it produced a small but significant (P < 0.05) increase in ir-corticosterone release. Denbufylline also increased the serum ir-LH concentration when given peripherally (0.2-0.6 microgram kg-1, i.p., P < 0.05) or centrally (100 ng kg-1, i.c.v., P < 0.05) but rolipram (1.6-200 micrograms kg-1, i.p. or 8 ng-1 microgram kg-1, i.c.v.) and BRL 61063 (0.25-30 micrograms kg-1, i.p. or 1 ng-1 microgram kg-1, i.c.v.) did not (P > 0.05). 3. In vitro rolipram (10 microM, P < 0.01), denbufylline (1 mM, P < 0.001) and BRL 61063 (1 and 10 microM, P < 0.05) stimulated the release of corticotrophin releasing hormone (ir-CRH-41) but lower concentrations of the drugs were without effect as also was BRL 61063 at 100 microM (P > 0.05); the rank order of potency was thus BRL 61063 > rolipram > denbufylline. The adenylyl cyclase activator forskolin (100 microM, P < 0.01) also stimulated the release of ir-CRH-41, producing effects which were additive with those of rolipram and denbufylline but not with those of BRL 61063. The secretory responses to forskolin (100 microM) were accompanied by a highly significant increase in the cyclic AMP content of the hypothalamic tissue (P < 0.005). Rolipram (10 microM) also significantly (P < 0.05) elevated the hypothalamic cyclic AMP but denbufylline (10 mM) and BRL 61063 (10 microM) did not. However, all three PDE-inhibitors potentiated the rise in cyclic AMP induced by forskolin (P < 0.05). None of the drugs tested, alone or in combination, modified the release of arginine vasopressin (ir-AVP) from the hypothalamus. 4. Rolipram (100 microM), denbufylline (100 microM) and BRL 61063 (100 microM) stimulated the release of corticotrophin (ir-ACTH) from pituitary tissue in vitro (P < 0.05) but in lower concentrations they were without significant effect. In addition, rolipram (10 microM, P < 0.05), denbufylline (0.1 microM, P < 0.05) and BRL 61063 (10 microM, P < 0.05) potentiated the significant (P < 0.05) rises in ir-ACTH secretion induced by forskolin (100 microM). Forskolin (100 microM) also produced a highly significant increase (P < 0.01) in the tissue cyclic AMP content which was further potentiated by rolipram (10 microM), denbufylline (10 microM) and BRL 61063 (10 microM) which, alone did not affect the cyclic AMP content of the tissue. 5. Since both denbufylline and BRL 61063 possess significant adenosine A1 receptor blocking activity, further studies examined the potential influence of these receptors on the secretion in vitro of CRH-41, AVP and ACTH. The release of ir-CRH-41 was increased significantly by adenosine deaminase (ADA, 5microml-1, P<0.05) and the A1-receptor antagonist, 1,3-dicyclopropyl-8-cyclopentylxanthine (DPCPX, 0.1-10nM, P<0.05). The responses to ADA were abolished by the A1 receptor agonist N6-cyclo-hexyladenosine (CHA, 100nM, P<0.05) which alone had no significant effect on ir-CRH-41 release. ADA (0.1-10microml-1) and DPCPX (1nM) had weak stimulant and inhibitory effects, respectively, on the release of ir-ACTH from the pituitary gland while CHA (0.1-10nM) was without effect. Ligand binding studies with [3H]-DPCPX as a probe demonstrated the presence of specific high affinity A1 binding sites in the hypothalamus (Kd=0.7nM; Bmax=367+/-32fmolmg-1 protein) and in the hippocampus (Kd=1nM; Bmax=1165 +/-145fmolmg-1 protein). In both tissues binding of the ligand was displaced by CHA (IC50=1nM (hypothalamus) and 2nM (hippocampus)), BRL 61063 (IC50=80nM (hypothalamus) and 100nM (hippocampus)) and denbufylline (IC50=5microM (hypothalamus) and 9microM(hippocampus)) but not by rolipram. 6.The results suggest that rolipram, denblufylline and BRL 61063 stimulate the HPA axis in the rat, acting at the levels of both the hypothalamus and the pituitary gland. Their actions may be explained, at least in part, by inhibition of PDE-4 but additional actions including blockade of hypothalamic adenosine A1 receptors by denbufylline and BRL 61063 cannot be excluded.     

Plasma and hepatic cholesterol levels and fecal neutral sterol excretion are altered in hamsters fed straw mushroom diets

The effect of the fruiting body and mycelium of Volvariella volvacea (straw mushroom) on the concentrations of plasma lipids, liver cholesterol, fecal neutral sterol and bile acid excretions was investigated in male Golden Syrian hamsters. The hamsters were fed a purified hypercholesterolemic diet (0.1% cholesterol, 10% fat) for 4 wk to elevate plasma lipid concentrations. Twelve hamsters with elevated plasma total cholesterol were randomly assigned to each treatment group: control (5% cellulose), mushroom fruiting body (5%) and mushroom mycelium (5%). After 4 wk of mushroom diet consumption, the plasma total cholesterol, HDL cholesterol, and combined VLDL + LDL cholesterol concentrations (mmol/L) were significantly lower than control in the group fed the fruiting body-diet (40, 38 and 43%, respectively) (P < 0.05). The liver cholesterol levels were significantly lower in both the mushroom fruiting body- and the mycelium-fed groups (28 and 21% in terms of concentration; 39 and 30% in terms of total content, respectively) (P < 0.05) than that in the control group. Fecal neutral sterol excretion in the mushroom fruiting body- and mycelium-fed groups was significantly higher (81 and 74%, respectively) (P < 0.05) than that in the control group. Although no significant differences (P > 0.05) in the excretion of fecal bile acids were observed among groups fed the mushroom diets and the control diet, the mushroom fruiting body diet-fed hamsters apparently had less bacterial degradation of cholic acid as indicated by a significantly greater proportion (P < 0.05) of fecal cholic acid than in controls. They also had a significantly lower proportion of fecal deoxycholic acid (P < 0.05). This study suggests that the fruiting body of the straw mushroom lowers elevated plasma cholesterol in hypercholesterolemic hamsters, whereas the mycelium does not.     

Differences in tissue fatty acids and cholesterol of swine from different genetic backgrounds

A review of 1,000 consecutive coronary angiograms, most of them performed for evaluation of angina pectoris, yielded 9 examples of congenital anomalies of the coronary arteries. In 2 cases the angina may have been due to malposition of the left coronary artery or one of its branches. There were 2 cases of aberrant origin of the circumflex artery from the right coronary artery, 2 cases of aberrant left anterior descending artery, 3 cases in which all three major coronary branches arose from the right aortic sinus, and 2 cases of coronary artery fistulas. Malposition of the coronary artery should be considered as a possible cause of angina.     

Dietary oxysterols are incorporated in plasma triglyceride-rich lipoproteins, increase their susceptibility to oxidation and increase aortic cholesterol concentration of rabbits

Early fatty streaks and advanced lesions are characterized by the deposition of cholesterol and cholesterol oxidation products (oxysterols). Oxysterols have been shown to be cytotoxic and pro-atherogenic compared to cholesterol and are found in cholesterol-rich processed foods. The consumption of dietary oxysterols may be significant in the onset and development of vascular disease. In order to study the short term effects of low levels of ingested dietary oxysterols on lipoprotein and aortic cholesterol and oxysterol levels, rabbits were fed either standard chow, chow supplemented with 1.0% oxidized cholesterol (containing 6% oxysterols), or 1.0% purified cholesterol (control). To determine the distribution and uptake of oxysterols after a 2-week dietary period, triglyceride-rich plasma lipoproteins, low density lipoproteins and aorta were analyzed by GC-MS. The concentration of 7beta-hydroxycholesterol was similar in all groups but the oxidized cholesterol-fed animals showed five times the concentration of 5alpha,6alpha-epoxycholesterol and double the level of 7-ketocholesterol in triglyceride-rich lipoproteins compared to the purified cholesterol-fed animals. The presence of 7-ketocholesterol in LDL was exclusive to animals fed the oxidized cholesterol diet. In addition, oxidation of triglyceride-rich lipoproteins was significantly greater in rabbits fed oxidized cholesterol compared to the pure cholesterol-fed animals. The oxidized cholesterol-fed animals also had a 64% increase in total aortic cholesterol, despite lower plasma cholesterol levels compared to the pure cholesterol control animals. Taken together these results suggest that dietary oxysterols may substantially increase the atherogenicity of lipoproteins.     

Dietary stearic acid reduces plasma and hepatic cholesterol concentrations without increasing bile acid excretion in cholesterol-fed hamsters

Although there is general agreement that saturated fatty acids elevate plasma cholesterol concentrations, the relative effects of individual fatty acids on cholesterol and bile acid metabolism are less clear. In this study, cholesterol and bile acid responses to diets enriched in different saturated fatty acids were investigated in hamsters. The six diets examined were as follows: 5% fat (g/100 g) enriched in palmitic acid (16:0) with no cholesterol, 5% fat 16:0-enriched, 0.05% cholesterol (wt/wt), and four diets containing 0.05% cholesterol and 15% fat with each diet enriched in lauric (12:0), myristic (14:0), palmitic (16:0), or stearic acid (18:0). Total plasma cholesterol concentration was significantly greater in hamsters fed the 14:0-enriched diet relative to those fed the 18:0-enriched diet (P < 0.05). Both plasma and liver cholesterol concentrations of hamsters fed 18:0 did not differ from those of the group fed no dietary cholesterol. In all instances, differences in total plasma cholesterol were accounted for within the HDL fraction; no significant treatment differences in VLDL or LDL cholesterol were found. Total daily fecal bile acid excretion was higher in hamsters fed the 15% fat 16:0 diet compared with those fed no dietary cholesterol (P < 0.05), but not significantly different from other treatment groups. There was greater deoxycholic acid excretion (P < 0.05) from hamsters fed the 14:0 and 16:0 diets compared with those fed the 18:0-enriched diet. Small intestinal + gallbladder bile acids, an index of pool size, did not differ significantly among the groups. The observed relative hypocholesterolemic effect of stearic acid was not mediated by increased bile acid excretion.     

Dietary fish oil (4 g daily) and cardiovascular risk markers in healthy men

Some epidemiological observations indicate that 1 to 2 weekly servings of fish prevent ischemic heart disease (IHD). This might be explained by an effect of the very-long-chain n-3 polyunsaturated fatty acids (n-3 VLCPUFA) of fish oil on lipid metabolism and/or the hemostatic system, both involved in IHD development. We studied the effect of incorporating natural fish oil (4 g daily equivalent to 0.91 g n-3 VLCPUFA and corresponding to one to two weekly servings of fatty fish) into the diet in a 4-week parallel, randomized, and double-blind trial of 47 healthy males aged 29 to 60 years. Sunflower oil was used as placebo. The fish oil had no significant effect on plasma lipids, apolipoproteins, lipoprotein(a), blood coagulation FVII, fibrinogen, endogenous fibrinolysis, beta-thromboglobulin, von Willebrand factor, glucose, or insulin in fasting blood samples. In nonfasting samples (n = 19), fish oil was associated with an approximately 30% decline in plasma triglycerides (P < .02) and a 9% decline in FVII protein (P < .05), whereas FVII coagulant activity and fibrinolysis were unaffected. In conclusion, our findings indicate that lowering of postprandial triglycerides is the only n-3 VLCPUFA effect that could contribute to primary prevention of IHD in healthy middle-aged men as assessed by currently measurable lipid and hemostatic risk markers.     

Soy protein has no hypocholesterolemic action in mice because it does not stimulate fecal steroid excretion in that species

We compared the effects of dietary soy protein isolate (SPI) and casein on plasma cholesterol level and fecal steroid excretion in rats, mice and hamsters. In rats, compared with casein, SPI significantly stimulated fecal steroid excretion in 9 out of 12 experiments with or without dietary cholesterol, whereas it suppressed plasma cholesterol level in 5 experiments and tended to suppress that, though not significantly, in 4 experiments. In mice, on the contrary, no significant difference was observed between the effects of casein and SPI on either the fecal steroid excretion or plasma cholesterol level in most of 12 experiments in which three different strains were tested. High-molecular-weight fraction of undigested residue of SPI exhibited marked hypocholesterolemic and steroid excretion-stimulating effects in rats and hamsters, whereas it showed only mild effects in mice. The species-dependent difference indicated the existence of inverse correlation between fecal steroid excretion and plasma cholesterol level and supported the view that in species like rat and hamster, but not mice, SPI lowers plasma cholesterol level by stimulating fecal steroid excretion.     

Effect of pectin on serum cholesterol, fecal bile acids and biliary lipids in normolipidemic and hyperlipidemic individuals

Pectin, 40-50 g/day for two weeks administered to nine normolipidemic and hyperlipidemic patients, had no effect on serum triglycerides but did cause a significant decrease in the serum total and unesterified cholesterol of hypercholesterolemic subjects in particular. This was associated with increased excretion of fecal bile acids and total steroids and increased concentration of plasma methyl sterols. Thus, the serum cholesterol reduction by pectin appears to be caused by increased cholesterol elimination into stools as bile acids which is then balanced by enhanced cholesterol synthesis. The composition of biliary bile acids and lipids was not changed and secondary bile acids and sterols decreased inconsistently in feces. The measurement of fecal dry weight suggested that the bulk of the pectin was degraded by bacteria during passage through the intestine. Consequently fecal mass and dry weight were not consistently increased, suggesting that pectin may not be an ideal fibre for increasing fecal bulk in functional colonic disorders.     

Dietary omega-3 polyunsaturated fatty acids promote colon carcinoma metastasis in rat liver

The effects of omega-3 polyunsaturated fatty acids (PUFAs) and omega-6 PUFAs on the development of experimentally induced colon carcinoma metastasis in rat liver were investigated quantitatively in vivo. Rats were kept on either a low-fat diet or on a fish oil (omega-3 PUFAs) or safflower oil (omega-6 PUFAs) diet for 3 weeks before the administration of colon cancer cells to the portal vein, until they were sacrificed at 1 or 3 weeks after tumor transplantation. At 1 week after transplantation, the fish oil diet had induced 7-fold more metastases (in terms of number and size) than had the low-fat diet, whereas the safflower oil diet had not affected the number and total volume of metastases. At 3 weeks after tumor transplantation, the fish oil diet and the safflower oil diet had induced, respectively, 10- and 4-fold more metastases (number) and over 1000- and 500-fold more metastases (size) than were found in the livers of rats on the low-fat diet. These differences were sex independent. Immunohistochemical analysis revealed that the immune system in the liver (Kupffer cells, pit cells, T cells, newly recruited macrophages, and the activation state of macrophages) did not play a significant role in this diet-dependent outgrowth of tumors. In conclusion, omega-3 and omega-6 PUFAs promote colon cancer metastasis in the liver without down-regulating the immune system. This finding has serious implications for the treatment of cancer patients with fish oil diet to fight cachexia.     

Dietary fat, trans fatty acids, and risk of coronary heart disease

Results from human feeding studies and recent large-scale epidemiologic surveys suggest that dietary trans fatty acids enhance the risk of developing coronary heart diseases. Despite a lack of accurate data regarding dietary intake of trans fatty acids, existing epidemiologic data and evidence from experimental feeding studies support the idea that lowering current intakes of trans fatty acids may lower the risk of coronary heart disease.     

Dietary modification of omega 6 fatty acid intake and its effect on urinary eicosanoid excretion

A group of women were fed two separate diets in a crossover study and urinary eicosanoids were quantified. One diet contained 3.1% of total energy (en%) as polyunsaturated fatty acids (3.0 en% linoleic acid) and the other contained 8.4 en% polyunsaturated fatty acids (8.3 en% linoleic acid). Carbohydrate replaced fat in the low-polyunsaturated-fat diet. No changes were observed in the urinary excretion of 6-oxo-prostaglandin F1 alpha, its 2,3-dinor metabolite or thromboxane B2 by subjects on either of the diets. Urinary 2,3-dinor-thromboxane B2 excretion was lower (206.5 ng/24 h) when subjects were fed the high-omega 6 polyunsaturated fatty acid diet when compared with the lower-omega 6 polyunsaturated fatty acid diet (275.3 ng/24 h). Conversely, urinary prostaglandin E2 was higher (139.2 ng/g creatinine) during the higher-omega 6 polyunsaturated fatty acid diet when compared with the lower-omega 6 polyunsaturated fatty acid diet (94.4 ng/g creatinine).