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Institut für Ernährungswissenschaften, Martin-Luther-Universität Halle-Wittenberg, Emil-Abderhaldenstraße 26, D-06108 Halle/Saale, Germany
1To whom correspondence should be addressed. E-mail: eder{at}landw.uni-halle.de.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-tocopherol equivalents (-toc)/kg] in relation to the concentration of 7ß-hydroxycholesterol (7ß-OH) in liver, plasma, LDL and erythrocytes of rats. In the rats whose diet contained salmon oil, the concentration of 7ß-OH was dependent on the dietary vitamin E concentration. Rats whose diet contained 10 mg -toc/kg had significantly higher concentrations of 7ß-OH in all samples studied than those whose diet contained 20, 40 or 240 mg -toc/kg. Increasing the dietary vitamin E concentration from 40 to 240 mg -toc/kg did not reduce the concentration of 7ß-OH in any samples. In the rats whose diet contained coconut oil, the concentration of 7ß-OH was independent of the dietary vitamin E concentration in all samples. The study shows that insufficient vitamin E in the diet increases the formation of 7ß-OH in rats fed salmon oil, whereas a dietary vitamin E supply in excess of the requirement does not lower 7ß-OH concentrations compared with an adequate vitamin E supply.
KEY WORDS: • 7ß-hydroxycholesterol • vitamin E • oxysterols • fish oil • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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) and are involved in the pathogenesis of arteriosclerosis (2
). The endogenous formation of oxysterols from cholesterol is promoted especially by peroxidation of polyunsaturated fatty acids (PUFA)2 (3
,4
). The susceptibility of membranes and lipoproteins to oxidation is determined primarily by the fatty acid composition of lipids and the concentrations of antioxidants, in particular tocopherols. Incorporation of highly unsaturated fatty acids from fish oil into lipids increases the susceptibility of tissues to oxidation, whereas an increased concentration of tocopherols lowers it (5
–7
). There is some evidence that the endogenous formation of oxysterols is influenced by the type of dietary fat and the ingestion of antioxidants (8
–12
). We are not aware of any studies investigating the interactions between the type of dietary fat and the level of the vitamin E supply in relation to the concentrations of oxysterols. The objective of our study was to determine the effect of the dietary vitamin E supply on the formation of oxysterols in tissues of rats fed fish oil or coconut oil. We considered a wide spectrum of vitamin E supply, from inadequate to excessive. Fish oil was chosen because it is often used in the prevention of arteriosclerosis due to its many favorable properties; coconut oil was used as a control fat with a very low PUFA content. From among the oxysterols formed in the body, we considered 7ß-hydroxycholesterol (7ß-OH) as a marker for the formation of oxysterols. The concentration of 7ß-OH in tissues reflects the endogenous, nonenzymatic formation of oxysterols fairly accurately (13
,14
). We determined the concentrations of 7ß-OH in plasma and LDL because this is where oxysterols are of particular pathophysiologic relevance. To gain further insight into the formation of oxysterols, we also measured the concentrations of 7ß-OH in liver and erythrocytes. |
MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male Sprague-Dawley rats (n = 72) with an initial body weight of 63 ± 5 g (mean ± SD) were obtained from Charles River (Sulzfeld, Germany). They were assigned to eight groups of nine rats each and housed in Macrolon cages in groups of 3 rats/cage in a room maintained at a temperature of 23°C and 50–60% relative humidity with lighting from 0600 to 1800 h. All experimental procedures described followed guidelines for the care and handling of laboratory animals and were approved by the council of Saxony-Anhalt.
Diets and feeding.
We used purified diets that were formulated according to the recommendations of the AIN (15
) for rat diets.3 The dietary fat, 100 g/kg coconut oil (Palmin, Hamburg, Germany) or 100 g/kg salmon oil (Caelo, Hilden, Germany) and the vitamin E concentration of the diet [10, 20, 40 or 240 mg -tocopherol equivalents (-toc)/kg] were varied according to a bifactorial design. The major fatty acids in coconut oil were (g/100 g total fatty acids): caprylic acid (8:0), 8.1; capric acid (10:0), 6.3; lauric acid (12:0), 45.6, myristic acid (14:0), 17.0; palmitic acid (16:0), 9.7; stearic acid (18:0), 4.5; oleic acid (18:1), 6.3; linoleic acid (18:2), 1.9. The major fatty acids in salmon oil were (g/100 g total fatty acids): myristic acid, 6.1; palmitic acid, 14.5; palmitoleic acid (16:1), 8.2; stearic acid, 3.0; oleic acid, 12.9; linoleic acid, 2.2; -linolenic acid [18:3(n-3)], 0.8; eicosanoic acid (20:1), 4.3; eicosapentaenoic acid [20:5(n-3)], 12.7; docosanoic acid (22:1), 4.5; docosapentaenoic acid [22:5(n-3)], 3.1; docosahexaenoic acid [22:6(n-3)], 10.0.
Vitamin E (as all-rac--tocopheryl acetate, Merck Eurolab, Darmstadt, Germany) was added to the diets at the expense of dietary fiber. To equalize the vitamin E concentrations of the diets, the native tocopherol levels of the two fats were analyzed. On the basis of the native concentrations of the fats, diets were supplemented individually with all-rac--tocopheryl acetate, allowing for a biopotency of 0.67% compared with -tocopherol. The diets were prepared weekly by solubilizing the all-rac--tocopheryl acetate in the fat and mixing it with the dry components and water. The diets were freeze-dried and stored at -20°C to prevent autoxidation of lipids, e.g., PUFA. The peroxide values of the dietary fats extracted from the diets with a mixture of hexane and isopropanol [3:2, according to (16
)], were determined at various times during storage of the diets. They were independent of the dietary vitamin E concentration and did not significantly increase during storage. Average peroxide values of the four vitamin E concentrations, measured according to official methods (17
), were 0.8 mEq O2/kg fat in the coconut oil diets and 8.6 mEq O2/kg fat in the salmon oil diets. The water content after freeze drying was <5 g/100 g diet. The experimental diets were fed for 42 d. Rats consumed the experimental diets and water, from nipple drinkers, ad libitum.
Sample collection.
After completion of the feeding period, the rats were starved overnight, anesthetized with diethyl ether and killed by decapitation. Blood was collected into heparinized polyethylene tubes (Sarstedt, Nürnbrecht, Germany). The liver was excised immediately and frozen with liquid nitrogen. Plasma was separated from blood by centrifugation (1100 x g, 10 min) at 4°C and stored at -80°C. Erythrocytes were washed three times with physiologic sodium chloride solution (9 g/L). Plasma lipoproteins were separated by step-wise ultracentrifugation (Mikro-Ultracentrifuge, Sorvall Products, Bad Homburg, Germany) at 900,000 x g at 4°C for 1.5 h. In the first step, the plasma density was adjusted to 1006 g/L by adding 0.3 mL of a solution containing 0.195 mol/L sodium chloride to 0.6 mL of plasma. After centrifugation, the upper portion of 0.3 mL, which contained the VLDL fraction was removed by suction and discarded. Then the density was adjusted to 1063 g/L by adding 0.3 mL of a solution containing 0.195 mol/L sodium chloride and 2.44 mol/L sodium bromide. After centrifugation, the upper portion of 0.3 mL which contained the LDL fraction was removed by suction and used for analysis of tocopherols and 7ß-OH. Concentrations of tocopherols and 7ß-OH in LDL were expressed per liter of plasma. Plasma, LDL, erythrocytes and liver were stored at -80°C until analysis.
Analytical methods.
The fatty acid composition of the experimental fats was determined by gas chromatography of fatty acid methyl esters (18
,19
). Liver, plasma, LDL and erythrocyte membrane 7ß-OH (Sigma-Aldrich, Steinheim, Germany) was determined using a quantitative gas chromatography-mass spectrometry (GC-MS) method with selective ion monitoring (20
). Liver and erythrocyte lipids were extracted with a mixture of hexane and isopropanol (3:2, v/v) (16
). After aliquots of the liver and erythrocyte lipid extracts were dried under a stream of nitrogen, 1 mol/L potassium hydroxide solution and 5-cholestane (Sigma-Aldrich, Steinheim, Germany) as internal standard were added, respectively, and the tubes flushed with nitrogen. To 0.5 mL of plasma or 0.25 mL of LDL fraction, 1 mol/L potassium hydroxide solution and 5-cholestane were added directly. After saponification overnight in the dark, double-distilled water was added and lipids were extracted with (peroxide-free) diethyl ether. The lipid extract was dried under a stream of nitrogen and then derivatized with bis-(trimethyl-silyl)-trifluoroacetamide (Sigma-Aldrich) and pyridine by heating samples at 60°C for 60 min. A Shimadzu QP-5000 GC-MS (Shimadzu, Duisburg, Germany) fitted with a DB 5 fused silica column (30 m, 0.25 mm i.d., 0.25-µm film thickness, J&W Scientific, Folsom, CA) was used for GC-MS analysis operating with selected ion monitoring. Helium was used as the carrier gas with a flow rate of 1 mL/min (40 cm/s). The sample (1 µL) was injected with a split ratio of 1:20. Peak identification was performed by retention time and ion fragmentation comparison with external standards. Two characteristic ions were used for 7ß-OH. Quantification was performed using calibration curves calculated with the internal standard. To control for the generation of 7ß-OH during treatment of the samples, controls that contained only pure cholesterol (2.4 µmol/assay) were assayed in parallel. The amount of 7ß-OH formed during treatment of the sample was below the detection limit of 0.02 nmol, indicating that <0.001% of the cholesterol was converted into 7ß-OH during sample treatment.
Concentrations of individual tocopherols in plasma, liver, LDL, erythrocytes and dietary oils were determined by HPLC (21
). Samples were mixed with 1 mL of 1% pyrogallol solution (in ethanol, absolute) and 150 µL of saturated sodium hydroxide solution. This mixture was heated for 30 min at 70°C, and tocopherols were extracted with n-hexane. Individual tocopherols of the extracts were separated isocratically using a mixture of n-hexane and 1,4 dioxane (96:4, v/v) as mobile phase and a LiChrosorb Si 60 column (5-µm particle size, 250 mm length, 4 mm i.d., Merck, Darmstadt, Germany) and detected by fluorescence (excitation wavelength: 295 nm; emission wavelength: 320 nm).
Statistics.
Data were subjected to ANOVA including the factors fat and vitamin E and the interactions between fat and vitamin E using the Minitab Statistical Software (Minitab, State College, PA). When variances were heterogeneous, data were transformed into their logarithms before ANOVA. For statistically significant F-values, individual means of the treatment groups were compared by Fisher’s multiple range test. Means were considered significantly different at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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In rats fed coconut oil, food intake was independent of the dietary vitamin E concentration. In those fed salmon oil, intake of the rats whose diet contained 10 mg -toc/kg was significantly lower than that of the groups whose diet contained 20, 40 or 240 mg -toc/kg (Table 1
). Daily body weight gains were affected by the interaction between the type of dietary fat and the dietary vitamin E supply. In rats fed coconut oil, daily body weight gains were independent of the dietary vitamin E concentration. In rats fed salmon oil, the rats whose diets contained 10 mg -toc/kg had significantly lower body weight gains than those whose diets contained 20, 40 or 240 mg -toc/kg.
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In rats fed diets containing 10 mg -toc/kg, the concentrations of tocopherols in liver, plasma, LDL and erythrocytes were 5–26 times higher in those whose diet contained coconut oil rather than salmon oil (Table 1
). Increasing the dietary vitamin E supply caused greater proportional increases in the tocopherol concentrations in all samples studied in rats fed salmon oil than in those fed coconut oil. Increasing the dietary vitamin E concentration from 10 to 240 mg -toc/kg led to 12- to 100-fold increases in the tocopherol concentrations in liver, plasma, LDL and erythrocytes in rats fed salmon oil, whereas in rats fed coconut oil, the increases in tocopherol concentrations of these tissues were only 2- to 9-fold. At the highest vitamin E concentration of 240 mg -toc/kg diet, the tocopherol concentrations of LDL and erythrocytes did not differ between rats whose diet contained salmon oil and those whose diet contained coconut oil. The tocopherol concentrations in liver and plasma, on the other hand, were more than twice as high in the rats whose diet contained coconut oil than in the rats whose diet contained salmon oil and a vitamin E concentration of 240 mg -toc/kg.
Concentrations of 7ß-OH.
At the lowest vitamin E concentration, the rats whose diet contained salmon oil had 2.4–6 times higher concentrations of 7ß-OH in the samples studied than those whose diet contained coconut oil (Table 2
). In the rats fed salmon oil, increasing the vitamin E concentration from 10 mg -toc/kg lowered the concentration of 7ß-OH in all samples studied. The lowest concentrations of 7ß-OH were found in liver and plasma of rats fed diets containing vitamin E levels of 40 and 240 mg -toc/kg and in LDL and erythrocytes in rats fed diets containing vitamin E levels of 20, 40 and 240 mg -toc/kg. In rats fed coconut oil, the concentrations of 7ß-OH in all samples studied did not differ due to vitamin E concentration. At vitamin E concentrations of 10 and 20 mg -toc/kg, the rats fed salmon oil had higher concentrations of 7ß-OH in all samples studied than those fed coconut oil. At vitamin E concentrations of 40 and 240 mg -toc/kg, concentrations of 7ß-OH differed between the rats fed coconut oil and salmon oil only in the liver, not in plasma, LDL or erythrocytes.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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). The extremely low tocopherol concentrations in the tissues of rats whose diet contained the lowest vitamin E concentration and salmon oil suggest a deficiency of vitamin E, which would also explain their slower growth compared with the rats from all other groups.
Low vitamin E concentrations in tissues and LDL, combined with ingestion of highly unsaturated fatty acids as found in fish oil, markedly increased concentrations of 7ß-OH. This is probably due to increased peroxidation of PUFA. High levels of highly unsaturated fatty acids and low tocopherol concentrations promote lipid peroxidation in tissues and lipoproteins (5
,6
). The observation that the concentrations of 7ß-OH in tissues were reduced by increasing the vitamin E supply confirms the importance of vitamin E as a protective factor against the formation of oxysterols. This is in agreement with several other studies that also suggested that the supply of antioxidants affects the formation of oxysterols (9
–13
). The study also shows very clearly, however, that an excessive supply of vitamin E does not further decrease the concentration of 7ß-OH. The study indicates that even at a very high intake of highly unsaturated fatty acids, relatively moderate vitamin E concentrations of 20–40 mg -tocopherol/kg diet are sufficient to protect the cholesterol in membranes and lipoproteins from oxidation.
The study also showed that the amount of vitamin E required to protect cholesterol from oxidation is distinctly lower in rats fed a fat with a low PUFA content than in rats fed a fat high in PUFA. At any given vitamin E supply, it is likely that fats low in PUFA lead to higher vitamin E concentrations, lower concentrations of PUFA in tissues and lipoproteins and therefore a reduced susceptibility to oxidation than do fats high in PUFA (23
).
Oxysterols in plasma and LDL are of particular pathophysiologic relevance. It has been shown that oxysterols as constituents of LDL are cytotoxic toward endothelial cells (24
,25
). What is more, a correlation has been established between the concentration of 7ß-OH in plasma and the etiology of arteriosclerosis (26
,27
). The observation that at adequate vitamin E levels of 40 or 240 mg -toc/kg diet, the concentrations of 7ß-OH in plasma and LDL were not greater in rats fed salmon oil than in those fed coconut oil suggests that fish oil likely does not influence the formation of oxysterols when the supply of vitamin E is sufficient.
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FOOTNOTES |
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-toc, -tocopherol equivalents; 7ß-OH, 7ß-hydroxycholesterol; GC-MS, gas chromatography-mass spectrometry; PUFA, polyunsaturated fatty acids. 
3 Diet composition: Experimental diets contained (g/kg): DL-methionine, 2; casein, 200; sucrose, 200; fat, 100; cellulose, 40; cornstarch, 398; mineral mixture, 40 (consisting of calcium carbonate, 7.56; dicalcium phosphate, 8.67; potassium chloride, 6.87; sodium bicarbonate, 3.77; magnesium oxide, 1.01; ferrous sulfate hydrate, 0.116; zinc oxide, 0.038; manganese oxide, 0.016; copper sulfate pentahydrate, 0.024; calcium iodate, 0.0032; sodium selenite pentahydrate, 0.0033); vitamin mixture 20 (consisting of all-trans-retinol, 1.34 mg; cholecalciferol, 25 µg; menadion sodium bisulfite, 7.5 mg; thiamine hydrochloride, 5 mg; riboflavine, 6 mg; pyridoxine hydrochloride, 6 mg; biotin, 0.2 mg; calcium pantothenate, 15 mg; nicotinic acid, 30 mg; vitamin B-12, 0.025 mg; folic acid, 2 mg; choline chloride, 1000 mg).
Manuscript received 5 August 2002. Initial review completed 26 August 2002. Revision accepted 6 September 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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21. Balz, M. K., Schulte, E. & Thier, H. P. (1993) Simultaneous determination of tocopherol acetate, tocopherols and tocotrienols by HPLC with fluorescence detection in foods. Fat Sci. Technol. 95:215-220.
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27. Salonen, J. T., Nyyssönen, K., Salonen, R., Porkkala-Sarataho, E., Tuomainen, T.-P., Diczfalusy, U. & Björkhem, I. (1997) Lipoprotein oxidation and progression of carotid atherosclerosis. Circulation 95:840-845.
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