Abstract P013: N-6 And N-3 Fatty Acid Cholesteryl Esters In Relation To Fatal Chd In A Dutch Adult Population: A Nested Case-control Study
Janette de GoedeW. M. Monique VerschurenJolanda M.A. BoerLisa D. M. VerberneDaan KromhoutJohanna M. Geleijnse
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Aim: Dietary polyunsaturated fatty acids (PUFA) are inversely related to coronary heart disease (CHD) in epidemiological studies. We examined the associations of plasma n-6 and n-3 PUFA in cholesteryl esters with fatal CHD in a nested case-control study. Methods We used data from two population-based cohort studies in Dutch adults aged 20-65 years. Blood sampling and data collection took place from 1987–1997 and subjects were followed for 8–19 years. We identified 279 incident cases of fatal CHD (235 fatal myocardial infarctions and 44 cardiac arrests) and randomly selected 279 controls, matched on age, gender, and enrollment date. Odds ratios (OR) with 95% confidence intervals (95%CI) were calculated per standard deviation (SD) increase of fatty acids in cholesteryl esters using multivariable conditional logistic regression models. Results After adjustment for confounders, the OR (95% CI) for fatal CHD per SD increase in plasma linoleic acid was 0.89 (0.74-1.06). Additional adjustment for plasma total cholesterol and systolic blood pressure attenuated this association (OR: 0.95; 95% CI: 0.78–1.15). Plasma arachidonic acid was not associated with fatal CHD (OR per SD: 1.11; 95% CI: 0.92-1.35). The ORs (95% CI) for fatal CHD for an SD increase in n-3 PUFA were 0.92 (0.74-1.15) for plasma alpha-linolenic acid and 1.06 (0.88-1.27) for plasma EPA-DHA. Conclusion In this Dutch adult population, arachidonic acid and n-3 PUFA in cholesteryl esters were not related to fatal CHD. Our data support findings from previous prospective studies showing a lower proportion of linoleic acid in plasma cholesteryl esters in CHD cases.Keywords:
Nested case-control study
Chinese hamster
Unsaturated fatty acid
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When cultured human umbilical vein endothelial cells are supplemented with linoleic acid, the arachidonic acid content of the cellular phospholipids is reduced approximately 35%. Most of the fatty acid compositional change occurs during the first 24 h. One factor responsible for this effect is the inability of the endothelial cells to convert appreciable amounts of linoleic to arachidonic acid, due to a fatty acid delta 6-desaturase deficiency. By contrast, these endothelial cultures contain delta 5- and delta 9-desaturase activity and are able to elongate long-chain polyunsaturated fatty acids. The other factor that contributes to the decrease in arachidonic acid is that high concentrations of linoleic acid reduce the incorporation of arachidonate into cellular phospholipids. Stearic acid, a long-chain saturate, does not produce any reduction, whereas eicosatrienoic acid is an even more effective inhibitor than linoleic acid. In spite of the fact that high concentrations of these polyunsaturates produced inhibition, the endothelial cells were found to efficiently incorporate exogenous arachidonic acid into cellular phospholipids and triglycerides. This may serve to compensate for the inability of these cells to synthesize arachidonic acid from linoleic acid. These findings suggest that the endothelium obtains arachidonic acid from an extracellular source, that this cannot be provided in the form of linoleic acid and, in fact, that high concentrations of linoleic acid actually may interfere with the ability of the endothelium to maintain an adequate supply of intracellular arachidonic acid.
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Linoleic acid, with a DRI of 12-17 g/d, is the most highly consumed polyunsaturated fatty acid in the Western diet and is found in virtually all commonly consumed foods. The concern with dietary linoleic acid, being the metabolic precursor of arachidonic acid, is its consumption may enrich tissues with arachidonic acid and contribute to chronic and overproduction of bioactive eicosanoids. However, no systematic review of human trials regarding linoleic acid consumption and subsequent changes in tissue levels of arachidonic acid has been undertaken.In this study, we reviewed the human literature that reported changes in dietary linoleic acid and its subsequent impact on changing tissue arachidonic acid in erythrocytes and plasma/serum phospholipids.We identified, reviewed, and evaluated all peer-reviewed published literature presenting data outlining changes in dietary linoleic acid in adult human clinical trials that reported changes in phospholipid fatty acid composition (specifically arachidonic acid) in plasma/serum and erythrocytes within the parameters of our inclusion/exclusion criteria.Decreasing dietary linoleic acid by up to 90% was not significantly correlated with changes in arachidonic acid levels in the phospholipid pool of plasma/serum (p = 0.39). Similarly, when dietary linoleic acid levels were increased up to six fold, no significant correlations with arachidonic acid levels were observed (p = 0.72). However, there was a positive relationship between dietary gamma-linolenic acid and dietary arachidonic acid on changes in arachidonic levels in plasma/serum phospholipids.Our results do not support the concept that modifying current intakes of dietary linoleic acid has an effect on changing levels of arachidonic acid in plasma/serum or erythrocytes in adults consuming Western-type diets.
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Linoleic acid, with a DRI of 12-17g/d, is the most highly consumed polyunsaturated fatty acid in the Western diet and is found in virtually all commonly consumed foods. The concern with dietary linoleic acid, being the metabolic precursor of arachidonic acid, is its consumption may enrich tissues with arachidonic acid and contribute to chronic and overproduction of bioactive eicosanoids. However, no systematic review of human trials regarding linoleic acid consumption and subsequent changes in tissue levels of arachidonic acid has been undertaken. In this study, we reviewed the human literature that reported changes in dietary linoleic acid and its subsequent impact on changing tissue arachidonic acid in erythrocytes and plasma/serum phospholipids. We identified, reviewed, and evaluated all peer-reviewed published literature presenting data outlining changes in dietary linoleic acid in adult human clinical trials that reported changes in phospholipid fatty acid composition (specifically arachidonic acid) in plasma/serum and erythrocytes within the parameters of our inclusion/exclusion criteria. Decreasing dietary linoleic acid up to 90% was not significantly correlated with changes in tissue arachidonic acid levels (p=0.39). Similarly, when dietary linoleic acid levels were increased six fold, no significant correlations with tissue arachidonic acid levels were observed (p=0.72). However, there was a positive relationship between dietary gamma-linolenic acid and arachidonic acid on changes in tissue arachidonic levels. Our results do not support the concept that modifying current intakes of dietary linoleic acid has an effect on changing tissue levels of arachidonic acid in adults consuming Western-type diets.
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The cytosolic fraction of human polymorphonuclear leukocytes precipitated with 60% ammonium sulfate produced 5-lipoxygenase products from [14C]arachidonic acid and omega-6 lipoxygenase products from both [14C]linoleic acid and, to a lesser extent, [14C]- and [3H]arachidonic acid. The arachidonyl 5-lipoxygenase products 5-hydroperoxy-6,8,11,14-eicosatetraenoic acid (5-HPETE) and 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) derived from [14C]arachidonic acid, and the omega-6 lipoxygenase products 13-hydroperoxy-9,11-octadecadienoic acid (13-OOH linoleic acid) and 13-hydroxy-9,11-octadecadienoic acid (13-OH linoleic acid) derived from [14C]linoleic acid and 15-hydroxyperoxy-5,8,11,13-eicosatetraenoic acid (15-HPETE), and 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE) derived from [14C]- and [3H]arachidonic acid were identified by TLC-autoradiography and by reverse-phase high-performance liquid chromatography (RP-HPLC). Products were quantitated by counting samples that had been scraped from replicate TLC plates and by determination of the integrated optical density during RP-HPLC. The arachidonyl 5-lipoxygenase had a pH optimum of 7.5 and was 50% maximally active at a Ca2+ concentration of 0.05 mM; the Km for production of 5-HPETE/5-HETE from arachidonic acid was 12.2 +/- 4.5 microM (mean +/- S.D., n = 3), and the Vmax was 2.8 +/- 0.9 nmol/min X mg protein (mean +/- S.D., n = 3). The omega-6 linoleic lipoxygenase had a pH optimum of 6.5 and was 50% maximally active at a Ca2+ concentration of 0.1 mM in the presence of 5 mM EGTA. When the arachidonyl 5-lipoxygenase and the omega-6 lipoxygenase were separated by DEAE-Sephadex ion exchange chromatography, the omega-6 lipoxygenase exhibited a Km of 77.2 microM and a Vmax of 9.5 nmol/min X mg protein (mean, n = 2) for conversion of linoleic acid to 13-OOH/13-OH linoleic acid and a Km of 63.1 microM and a Vmax of 5.3 nmol/min X mg protein (mean, n = 2) for formation of 15-HPETE/15-HETE from arachidonic acid.
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In the present study we measured the bleeding times in fourteen Aborigines (10 diabetic, 4 non-diabetic) before and after 2 weeks on a diet of tropical seafood (rich in both arachidonic acid and the omega 3 PUFA), followed by 3 weeks on a diet in which kangaroo and freshwater fish (linoleic and arachidonic acid-rich) were the major fat sources. Both diets were very low in fat. Bleeding times increased in all subjects after the 2 weeks of tropical seafood and continued to rise on the mixed diet. The increase over 5 weeks from 4.1 +/- 0.4 to 5.9 +/- 0.4 min was highly significant (p less than 0.01). Due to the extreme isolation of the study location it was only possible to measure the plasma fatty acid composition at the beginning and end of the study. The concentration of arachidonic acid in the plasma lipids doubled whereas that of linoleic acid was almost halved, despite the fact that the diet in the second part of the study contained considerably more linoleic than arachidonic acid. That there appeared to be preferential incorporation of arachidonic acid into the plasma lipids is further supported by the observation that the rise in arachidonic acid in the cholesterol ester and phospholipid fractions was almost exactly counter-balanced by the fall in linoleic acid. In conclusion, the present study demonstrated a rise in bleeding time associated with an increased concentration of arachidonic acid and decreased concentration of linoleic acid in plasma lipids, and suggests that the mechanism by which diet modulates haemostatic function may be more complex than currently assumed.
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