Kristian S. Bjerve

Effect of eicosapentaenoic and docosahexaenoic acids on blood pressure in hypertension: a population-based intervention trial from the Tromsø study.

Studies of whether polyunsaturated fatty acids in fish oil--in particular, eicosapentaenoic and docosahexaenoic acids--lower blood pressure have varied in design and results. We conducted a population-based, randomized, 10-week dietary-supplementation trial in which the effects of 6 g per day of 85 percent eicosapentaenoic and docosahexaenoic acids were compared with those of 6 g per day of corn oil in 156 men and women with previously untreated stable, mild essential hypertension. The mean systolic blood pressure fell by 4.6 mm Hg (P = 0.002), and diastolic pressure by 3.0 mm Hg (P = 0.0002) in the group receiving fish oil; there was no significant change in the group receiving corn oil. The differences between the groups remained significant for both systolic (6.4 mm Hg; P = 0.0025) and diastolic (2.8 mm Hg; P = 0.029) pressure after control for anthropometric, lifestyle, and dietary variables. The decreases in blood pressure were larger as concentrations of plasma phospholipid n-3 fatty acids increased (P = 0.027). Dietary supplementation with fish oil did not change mean blood pressure in the subjects who ate fish three or more times a week as part of their usual diet, or in those who had a base-line concentration of plasma phospholipid n-3 fatty acids above 175.1 mg per liter. We conclude that eicosapentaenoic and docosahexaenoic acids reduce blood pressure in essential hypertension, depending on increases in plasma phospholipid n-3 fatty acids.

Alpha-linolenic acid deficiency in patients on long-term gastric-tube feeding: estimation of linolenic acid and long-chain unsaturated n-3 fatty acid requirement in man

Alpha-linolenic acid deficiency is described in four adults fed by gastric tube. In plasma and erythrocytes, total lipid 20:3n-9 was slightly increased but total n-6 fatty acids, arachidonic acid, and dihomo-gamma-linolenic acid were normal. Total n-3 fatty acids, 18:3n-3, 20:5n-3, 22:5n-3, and 22:6n-3 were decreased in both plasma and erythrocytes. Patients had a slight but definite scaly dermatitis, which disappeared with essential fatty acids supplementation. Simultaneously, levels of 18:3n-3, 20:5n-3, 22:5n-3, 22:6n-3, 20:3n-9, and total n-3 fatty acids became normal while 18:2n-6, 20:3n-6, 20:4n-6, and total n-6 acids were unchanged or slightly lowered. Estimated minimal daily requirement of linolenic acid and of long-chain unsaturated n-3 acids in adults is approximately 0.2-0.3% and 0.1-0.2%, respectively, of total energy intake. Results suggest that conversion of linolenic acid to 22:6n-3 is increased in linolenic acid deficiency.

The Ca2+-dependent biosynthesis of lecithin, phosphatidylethanolamine and phosphatidylserine in rat liver subcellular particles

Abstract 1. 1. The Ca2+-dependent incorporation of choline, ethanolamine and l -serine into rat liver phospholipids has been studied in vitro. The incorporation was located exclusively in the microsomal fraction. 2. 2. No incorporation took place in the presence of EDTA. The optimal Ca2+ concentration was found to increase with decreasing pH, and vice versa. At pH 8.8 and 0.16 mM Ca2+ the Km values of choline, ethanolamine and l -serine were 2.3 · 10-5, 9.5 · 10-6 and 6.2 · 10-5 M, respectively. At pH 7.5 the Km and V for both choline and ethanolamine increased with increasing Ca2+ concentration. At pH 8.8 high Ca2+ concentrations were inhibitory. The Km and V of l -serine showed no significant changes. 3. 3. Choline incorporation was competitively inhibited by ethanolamine and l -serine; incorporation of l -serine was competitively inhibited by choline and ethanolamine. In contrast, ethanolamine incorporation was inhibited noncompetitively by l -serine and uncompetitively by choline. This indicates that the Ca2+-stimulated incorporation of choline, ethanolamine and l -serine does not occur via a single common phosphatidyl-enzyme complex. 4. 4. Ethanolamine is incorporated preferentially into polyunsaturated phosphatidylethanolamine species in rat liver microsomes. The rate of incorporation into hexa-unsaturated species was twice that into mono- and di-unsaturated species, while choline was incorporated 10–15 times more rapidly into the hexa-unsaturated species. 5. 5. The results show that the incorporation rate of l -serine found in vitro can account for the rate of phosphatidylserine synthesis observed in vivo. The Ca2+-dependent mechanism thus seems to be the major pathway of phosphatidylserine synthesis in the liver. In contrast, the synthesis of lecithin and phosphatidylethanolamine via this mechanism must be quantitatively negligible. 6. 6. A metabolic scheme is discussed which implies interconversion of the respective phospholipids.

Omega-3 fatty acids: essential fatty acids with important biological effects, and serum phospholipid fatty acids as markers of dietary omega 3-fatty acid intake.

Serum phospholipid eicosapentaenoic (PL-EPA) and docosahexaenoic acid (PL-DHA) concentrations are associated with the dietary intake of omega 3 fatty acids. PL-EPA and PL-DHA concentrations measured 4 y apart in 211 diabetic patients were highly correlated, with Spearman correlation coefficients of 0.49 (p = 0.0001) and 0.64 (p = 0.0001), respectively. PL-DHA was positively associated with Bayley psychomotor and mental developmental indexes (PDI and MDI, respectively) in preterm infants. Using multiple-regression analysis, 64% (R2 = 0.639; p = 0.0001) of PDI variance was explained by 1/DHA and weight at 1 y, whereas 82% (R2 = 0.816; p = 0.0001) of MDI variance was explained by weight at 1 y, Apgar score, 1/DHA, and 1/EPA. 1/DHA was negatively correlated with PDI and MDI, whereas 1/EPA was positively correlated with MDI. The results suggest that infant formulas should contain preformed DHA, and that a too-high supply of EPA in addition to DHA might be harmful in preterm infants.

The enteral bioavailability of eicosapentaenoic acid and docosahexaenoic acid is as good from ethyl esters as from glyceryl esters in spite of lower hydrolytic rates by pancreatic lipase in vitro

Enteral absorption by healthy male volunteers of cis-5,8,11,14,17-eicosapentaenoic acid (20:5(n-3), EPA) and cis-4,7,10,13,16,19-docosahexaenoic acid (22:6(n-3), DHA) from an ethyl ester enriched in EPA and DHA (K85) and from natural fish oil (TG30) was found to be similar after intake of equivalent doses. Thus, after administration twice daily for 14 days, the amounts of EPA and DHA in total serum lipids and in serum phospholipids were essentially identical for the two ester forms of the n-3 fatty acids. A dose-dependent relationship between intake and total phospholipid serum levels was observed for EPA, which increased 6.5-12-fold and 4.8-9-fold, respectively, but DHA reached a plateau at 2-2.5-fold over the control after supplementation. Arachidonic acid (AA) did not change significantly in total serum lipids, but fell 10-20% in serum phospholipids. The supplementation resulted in a 6.3-11-fold increase in the EPA/AA ratio. A significant and dose-dependent 25-45% reduction in linoleic acid (18:2(n-6), LA) was found in serum phospholipids, while a smaller decrease was observed in total serum lipids. 20:3(n-6), 20:3(n-9) and 22:5(n-6) also decreased significantly in serum phospholipids. Saturated fatty acids remained essentially unchanged. Some 35-47% decrease in serum triacylglycerols and approx. 10% decrease in cholesterol levels were also observed. In spite of the similar serum levels of EPA and DHA obtained in vivo, in vitro hydrolysis by porcine pancreatic lipase of K85 was 3-fold slower than hydrolysis of a glyceryl ester (TG85) similarly enriched in EPA and DHA, and 15-fold slower than the hydrolysis of the 3-fold less enriched TG30 with EPA and DHA predominantly in the 2-position. Under similar conditions release of AA from glyceryl ester and ethyl ester was essentially similar and approx. 1.5-fold faster than release of EPA and DHA from ethyl esters. In vitro hydrolysis of olive oil was 1.8-fold faster than hydrolysis of a natural fish oil (TG30) under similar conditions. Thus, the order of the rates of hydrolyses was olive oil > TG30 > TG85 > triarachidonin > LA ethyl ester > AA ethyl ester > ethyl ester K85. Our results show that in spite of differences in the rate of hydrolysis by lipase in vitro, the enteral absorption of EPA and DHA is as least as good from a synthetic ethyl ester highly enriched in EPA and DHA as it is from a natural triacylglycerol containing equivalent amounts of these fatty acids.

Plasma Saturated and Linoleic Fatty Acids Are Independently Associated With Blood Pressure

The role of individual fatty acids in blood pressure regulation is unclear. We studied the cross-sectional relationship of blood pressure, total plasma phospholipid fatty acid concentrations, and proportions of individual fatty acids among participants in a population study. Blood pressure was measured automatically, and plasma phospholipid fatty acids were determined by gas-liquid chromatography in 4033 healthy men 40 to 42 years old. Significant positive linear associations existed between total fatty acids and saturated fatty acids and blood pressure, whereas polyunsaturated linoleic acid was inversely associated with blood pressure. In multiple regression analyses, a 2-SD increase in total fatty acids was associated with an increase of 6.0 (95% CI, 5.1 to 6.8) mm Hg systolic blood pressure. A 2-SD increase in saturated palmitic acid was associated with 1.4 (95% CI, 0.5 to 2.3) mm Hg increase in systolic blood pressure. In contrast, a 2-SD increase in polyunsaturated linoleic acid was associated with a 1.9 (95% CI, 1.0 to 2.8) mm Hg decrease in systolic blood pressure. We conclude that plasma levels of total fatty acids, saturated fatty acids, and polyunsaturated linoleic acid are independently associated with blood pressure. The present study supports the hypothesis that the composition of dietary fat influences blood pressure.

Vitamin D and disease activity in multiple sclerosis before and during interferon-β treatment

Objective: Studies based on deseasonalized vitamin D levels suggest that vitamin D may influence the disease activity in multiple sclerosis (MS), and high doses are suggested as add-on treatment to interferon-β (IFN-β). Seasonal fluctuation of vitamin D varies between individuals, thus the relationship to disease activity should preferentially be studied by repeated and simultaneous vitamin D and MRI measurements from each patient. Methods: This was a cohort study comprising 88 patients with relapsing-remitting MS who were followed for 6 months with 7 MRI and 4 25-hydroxyvitamin D measurements before initiation of IFN-β, and for 18 months with 5 MRI and 5 25-hydroxyvitamin D measurements during IFN-β treatment. Results: Prior to IFN-β treatment, each 10 nmol/L increase in 25-hydroxyvitamin D was associated with 12.7% (p = 0.037) reduced odds for new T1 gadolinium-enhancing lesions, 11.7% (p = 0.044) for new T2 lesions, and 14.1% (p = 0.024) for combined unique activity. Patients with the most pronounced fluctuation in 25-hydroxyvitamin D displayed larger proportion of MRI scans with new T1 gadolinium-enhancing lesions (51% vs 23%, p = 0.004), combined unique activity (60% vs 32%, p = 0.003), and a trend for new T2 lesions (49% vs 28%, p = 0.052) at the lowest compared to the highest 25-hydroxyvitamin D level. No association between 25-hydroxyvitamin D and disease activity was detected after initiation of IFN-β. HLA-DRB1*15 status did not affect the results. Conclusion: In untreated patients with MS, increasing levels of 25-hydroxyvitamin D are inversely associated with radiologic disease activity irrespective of their HLA-DRB1*15 status.

ω-3 Fatty Acid Treatment in Multiple Sclerosis (OFAMS Study): A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE To investigate whether ω-3 fatty acids reduce magnetic resonance imaging (MRI) and clinical disease activity in patients with multiple sclerosis, both as monotherapy and in combination with interferon beta-1a treatment. DESIGN Multicenter, randomized, double-blind, placebo-controlled clinical trial conducted from 2004 to 2008. SETTING Thirteen public neurology departments in Norway. PARTICIPANTS Patients aged 18 to 55 years with active relapsing-remitting multiple sclerosis, with a disability score equivalent to 5.0 or less on the Kurtzke Expanded Disability Status Scale. Ninety-two patients were randomized to ω-3 fatty acids (n = 46) or placebo capsules (n = 46). INTERVENTIONS Administration of 1350 mg of eicosapentaenoic acid and 850 mg of docosahexaenoic acid daily or placebo. After 6 months, all patients in addition received subcutaneously 44 μg of interferon beta-1a 3 times per week for another 18 months. MAIN OUTCOME MEASURE The primary outcome measure was MRI disease activity as measured by the number of new T1-weighted gadolinium-enhancing lesions during the first 6 months. Secondary outcome measures included MRI disease activity after 9 months and 24 months, relapse rate, disability progression, fatigue, quality of life, and safety. RESULTS The cumulative number of gadolinium-enhancing MRI lesions during the first 6 months were similar in the ω-3 fatty acids and placebo groups (median difference, 1; 95% CI, 0 to 3; P = .09). No difference in relapse rate was detected after 6 (median difference, 0; 95% CI, 0 to 0; P = .54) or 24 (median difference, 0; 95% CI, 0 to 0; P = .72) months. The proportion of patients without disability progression was 70% in both groups (P > .99). No differences were detected in fatigue or quality-of-life scores, and no safety concerns appeared. Serum analyses of fatty acids showed an increase in ω-3 fatty acids (mean difference, 7.60; 95% CI, 5.57 to 7.91; P < .001) in the patients treated with ω-3 fatty acids compared with the placebo group. CONCLUSION No beneficial effects on disease activity were detected from ω-3 fatty acids when compared with placebo as monotherapy or in combination with interferon beta-1a. Magnetic resonance imaging disease activity was reduced as expected by interferon beta-1a. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00360906.

Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease

It is known that the metabolism of homocysteine (Hcy) depends on the vitamins B6, B12 and folate, and furthermore that metformin reduces serum vitamin B12 levels. In order to investigate whether metformin treatment affects serum total Hcy (tHcy) levels we performed an open, prospective, randomised study in 60 non-diabetic male patients with cardiovascular disease. After a 4-week run-in period with lovastatin 40 mg day-1, and diet and lifestyle advice, patients were randomised into two groups, both continuing the run-in treatment. One group received metformin up to 2000 mg day-1, whereas the control group got no additional treatment. After 12 and 40 weeks of metformin treatment, tHcy levels increased moderately but significantly by 7.2% (p < 0.05) and 13.8% (p < 0.05) in the metformin group relative to the control group, whereas serum vitamin B12 levels decreased by 13.4% (p < 0.0005) and 17.7% (p < 0.0005), respectively. Serum folate levels did not change after 12 weeks, but decreased by 8.0% after 40 weeks (p = 0.061) relative to the control group. Serum levels of total cysteine and methylmalonic acid (MMA) did not change. In conclusion, metformin treatment increased tHcy levels and decreased levels of vitamin B12 and folate. Since MMA levels were unchanged, it remains an open question whether the increase in tHcy levels is secondary to reduced vitamin B12 levels, folate levels or a combination of both.

Polyunsaturated Fatty Acids in Serum Phospholipids and Risk of Breast Cancer: A Case-control Study from the Janus Serum Bank in Norway

We have tested the hypothesis that specific polyunsaturated fatty acids (PUFA) of the n-3 and n-6 families, as measured in serum phospholipids, are negatively associated with the risk of breast cancer. The study is based on serum samples from women who have donated blood to the Janus serum bank at the University Hospital in Oslo, Norway. It consists of sera from 87 women who developed breast cancer (cases) subsequent to blood donation and 235 women who were free of any diagnosed cancer (controls), but were of similar age and had similar blood storage time as the cases. We measured fatty acids (monounsaturated, polyunsaturated and saturated) in serum phospholipids, and made comparisons between cases and controls. The results showed that there was an inverse relation between the n-6 PUFA linoleic acid (18:2n-6) and risk of breast cancer, but this association was restricted to women who were 55 years and younger. In this age group, the relative risk (odds ratio) of women in the highest quartile of linoleic acid was 0.4 (95% confidence limits, 0.2 and 1.0) compared with women in the lowest quartile, and there was a negative trend over quartiles of linoleic acid (Mantels chi for trend = -2.49, P < 0.02). No association was noted between the n-3 PUFA of marine oil origin and breast cancer risk. If the measured concentration of linoleic acid in serum phospholipids reliably reflects dietary intake, these data suggest that linoleic acid in the diet may decrease breast cancer risk among women at premenopausal and perimenopausal age. No similar association with n-3 unsaturated fatty acids was observed. It is noteworthy that none of the measured fatty acids (saturated or unsaturated) showed a positive association with breast cancer risk.