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3 Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, DK-1958 Frederiksberg C, Denmark and 4 The Nutritional Immunology Group, Center for Biological Sequence Analysis, BioCentrum, Technical University of Denmark, DK-2800 Lyngby, Denmark
* To whom correspondence should be addressed. E-mail: ctd{at}life.ku.dk.
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ABSTRACT |
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 TOP ABSTRACT IntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Atherosclerosis is recognized as an inflammatory disease (13) and besides the well-established risk markers, a number of inflammatory markers have been linked to CVD risk. C-reactive protein (CRP) fluctuates widely in response to tissue damage and infection and may be a long-term marker of low-grade inflammation (14). CRP is induced by interleukin (IL)-6 and elevated plasma levels of both have been shown to be independently associated with increased risk of CVD events (14–16). Cluster of differentiation antigen 40 (CD40) and its ligand CD40L, which are involved in T- and B-cell activation, have been found in human atherosclerotic plaques and associated with thrombotic risk (17). Soluble vascular cell adhesion molecule-1 (VCAM-1) has also been reported to be elevated in atherosclerotic lesions, but its role as a CVD risk marker is controversial (18,19). The expression of VCAM-1 is induced by CD40L along with other adhesion molecules and selectins (20). During atherogenesis, these molecules and monocyte chemoattractant protein-1 (MCP-1) from endothelial cells and others promote monocyte recruitment and migration through the endothelium (13,21). In intima, monocytes differentiate into macrophages that play a key role in plaque development by engulfing oxidized LDL (oxLDL). In contrast, adiponectin, a recently discovered peptide secreted from adipocytes, may have antiinflammatory properties and has been shown to be inversely related to fat mass, type II diabetes, and myocardial infarction (22).
A number of randomized trials have investigated the effects of fish oils on classical CVD risk markers, but the effects on risk markers related to inflammation and vascular wall function are not well described. Moreover, to our knowledge, it has not been investigated how fish oil affects the overall CVD risk profile in healthy people at different background LA intakes. Here, we evaluated the effects of 8-wk fish oil supplementation in combination with a high- or low-LA intake on traditional and emerging markers of CVD risk.
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Materials and Methods |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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The study protocol was approved by the Scientific Ethical Committee of Frederiksberg and Copenhagen (no. KF 01267804) and registered in the NIH clinical trial database (ClinicalTrials.gov, no. NCT00266292). Eligible persons were apparently healthy males aged 18–40 y with no chronic diseases, no regular medication, and no strong allergies who were smoking <5 cigarettes per week, exercising strenuously <7 h/wk, eating homemade meals 
5 d/wk, and consumed butter, margarine, and/or oil daily. Blood donation or dietary supplements were not allowed 2 mo before or during the study. Informed written consent was obtained from all participants. Two participants left the study during the intervention period and 64 participants completed the study.
Intervention and compliance.
The median capsule oil consumption during the intervention was 4.4 mL/d (range 2.0–5.6 mL/d) in both groups, corresponding to a median intake of 3.1 g/d (n-3) LCPUFA (1.8 g/d eicosapentaenoic acid [EPA, 20:5(n-3)] + 0.2 g/d docosapentaenoic acid [DPA, 22:5(n-3)] + 1.1 g/d docosahexaenoic acid [DHA, 22:6(n-3)]) in the FO groups and 3.7 g/d oleic acid [18:1(n-9)] in the OO groups. In the fat intervention, the participants were told to replace their habitual fats used for cooking, baking, and on bread with those we provided. The mean contents per 100 g of the S/B and R/K fats were, respectively: 42.8 g and 18.0 g PUFA (40.3 g and 12.7 g LA; 2.4 g and 5.3 g 
-linolenic acid [18:3(n-3)]); 22.6 g and 42.2 g MUFA; and 10.8 g and 15.9 g SFA [see (23)]. Based on the dietary records, the median consumption of the provided intervention fats was 3.4 g/d spread (0.0–32.5 g/d) and 10.3 g/d oil (0.0–52.5 g/d) and the 4 groups did not differ (P > 0.78; Kruskall-Wallis test). The oils and spreads were kind gifts from Aarhus United Denmark A/S, Unilever Danmark A/S, and Arla Foods amba and the capsules were kindly provided by Pharma Nord ApS. The fats and capsules were packed in identical, neutral containers, randomization was done separately for the fat and capsule intervention, and all participants and investigators were unaware of the allocations until the end of data analysis. As a measure of compliance and tissue incorporation of the FO, the fatty acid composition of peripheral blood mononuclear cells (PBMC) was analyzed. EPA incorporation of PBMC has been shown to be maximal after 2–4 wk supplementation (24).
Measurements. We measured weight and height using standard procedures. BP was measured in the supine position after a 10-min rest with a volume-oscillometric device (Artcomp, Criticon). All BP recordings were performed on the right arm. Venous blood was sampled from the left forearm after 10 min of supine rest. We instructed the participants to fast for 12 h (except for 0.5 L water), not take any medication or drink alcohol 24 h prior to blood sampling, avoid exercise 36 h before sampling, not to smoke the last week, and to have the same meal every night before the blood sample was taken. We checked these criteria at every visit. After the intervention, we also measured BP, HR, and TAG postprandially, i.e. 2.5 h after a standardized breakfast meal, consumed in 15 min and kindly provided by Arla Foods amba and Lantmännen Schulstad A/S. The meal contained 4000 kJ and 50 g fat (27 g SFA).
Laboratory analyses. EDTA blood was centrifuged at 3000 x g; 15 min at 20°C within 2 h and plasma was isolated for analysis of cholesterol, TAG, CRP, IL-6, and oxLDL. After 30 min of clotting, serum was isolated by the same centrifugation procedure for analysis of glucose and CD40L concentrations. Heparinized blood was drawn on ice and plasma obtained by centrifugation at 2000 x g; 7 min at 4°C for analysis of insulin, MCP-1, VCAM-1, P-selectin, and adiponectin. Blood sample aliquots for analysis of CRP and glucose were frozen at –20°C and the others were frozen at –80°C. Maximal storage time before analysis was 9 mo.
Plasma concentrations of total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), TAG, and glucose were determined by an automated enzymatic colorimetric principle with commercial kits (Roche Diagnostics) on Cobas Mira Plus (Roche Diagnostic System). Plasma CRP was analyzed with a highly sensitive assay. Together with plasma insulin, this was done with chemiluminescent immunometric kits on Immulite 1000 (all from Diagnostics Product). IL-6, VCAM-1, P-selectin, CD40L, and adiponectin concentrations were determined by ELISA kits from R&D Systems, oxLDL with kits from Mercodia, and MCP-1 with kits from Diaclone. Fibrinogen concentrations were determined by an automated clot assay on an ACL 300 analyzer (ACL Instrumentation Laboratories Scandinavia).
All samples from each person were analyzed on the same day and in the same assay. Inter- and intra-assay variation (expressed as CV%) were 0.7 and 0.8% (TC), 2.7 and 2.6% (LDL-C), 2.3 and 1.9% (HDL-C), 0.7 and 1.8% (TAG), 1.3 and 1.2% (glucose), 7.4 and 6.7% (insulin), not applicable and 2.6% (fibrinogen), 5.1 and 7.3% (CRP), 28 and 7% (MCP-1), 3.5 and 6.6% (VCAM-1), 3.8 and 7.0% (P-selectin), 5.8 and 3.9% (oxLDL), 3.7 and 3.3% (CD40L), and 29 and 10% (adiponectin). According to the manufacturer, IL-6 inter- and intra-assay variation was 11 and <10%. Samples (10%) that were below the CRP detection limit of 0.1 mg/L were defined as 0.05 mg/L. Two CRP and IL-6 values were excluded due to CRP concentrations >10 mg/L, indicating acute inflammation (25).
PBMC isolation and fatty acid analysis were conducted as described in (23). In brief, PBMC were isolated from freshly drawn heparinized blood by density centrifugation and lipids were extracted by the Folch procedure (26) and identified by GC.
Statistics. As a measure of steady-state insulin resistance, the homeostasis model assessment (HOMA) index was calculated as [insulin concentration (pmol/L)] x [glucose concentration (mmol/L)]/22.5 (27). Plasma TAG, TC:HDL-C, CRP, MCP-1, VCAM-1, and CD40L were logarithmically transformed and plasma IL-6 was inversely square-root transformed before analysis. Comparisons among the 4 intervention groups at baseline were done in 1-way ANOVA with Tukey's post hoc test. Comparisons after the intervention were done in ANCOVA with fat (S/B or R/K) and capsule (FO or OO) as fixed factors and adjustment for values at baseline, after checking for interaction. Smoking (yes/no) and weight changes during the intervention were also tested as possible confounders. Within-group changes were tested with paired t tests. Bivariate correlations were done with Pearson's correlation analysis. All data were analyzed with SPSS software (version 14.0) and are presented in the text as means ± SD or range or mean (95% CI). P < 0.05 was considered significant. Sample sizes of 15 per group had been calculated to give sufficient power (β = 0.80) to detect differences of 1 SD in the outcome variables.
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Results |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Discussion |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Davidson (28) recently proposed a mechanistic model for the hypotriglyceridemic effect of (n-3) LCPUFA. This involves the coordinated action of at least 4 metabolic nuclear receptors (including peroxisome proliferator-activated receptors and X receptors), which overall redirects fat from storage toward oxidation, thereby reducing VLDL synthesis and TAG concentrations. In the present study, the TAG-lowering effect of fish oil was numerically greatest, although not statistically significant, in the group that also received the low-LA fats (Fig. 1). This may indicate a combined effect of FO and R/K or may be due to the tendency for the FO+R/K group to have a numerically higher TAG concentration at baseline (Table 2). Two systematic reviews based on randomized controlled trials reported that the TAG-lowering effect of fish oil depends on TAG concentrations at baseline (5,29).
The high-LA fats (S/B) did not decrease plasma cholesterol levels; rather, the opposite tendency was seen (P = 0.10 for TC). Based on the equations of Hegsted et al. [reviewed in (30)], the achieved 3 E% increase in dietary LA would be expected to lower TC by only <0.1 mmol/L. Also, in other studies where comparable differences in the (n-6) PUFA intake (31) or larger differences in the LA intake (32) were investigated, plasma cholesterol was not affected. Although modest increases in LDL-C and HDL-C concentrations have been observed, the lack of effect of fish oil on cholesterol variables is well known (5,29).
Fish oil was shown to lower ambulatory BP in 2 meta-analyses (6,33) but mainly in older, hypertensive subjects, whereas the effect in young, normotensive subjects is negligible (6,33). Fish oil has also been shown to reduce HR (7), but even with 24-h continuous HR measurements, little effect is seen in persons with an already low HR, i.e. < 
70 beats/min (7,34), as in our study (data not shown). Fish oil has been speculated to impair the regulation of glucose metabolism in diabetics. However, consistent with our data, fish oil did not affect fasting insulin or glucose or glucose tolerance in healthy men (35), also after taking into account the (n-6):(n-3) PUFA ratio in the habitual diet (36). In another study, insulin sensitivity was not affected by fish oil either at high or low (n-6) PUFA intake (31). Fasting levels and the HOMA index, as used in our study, are not optimal measures of insulin sensitivity. However, our data support the literature, because the slight effects of the low-LA fats on insulin and the HOMA index were explained by changes in body weight.
Neither of the interventions clearly affected any of the emerging inflammatory CVD risk markers. Although a study in rheumatoid arthritis patients showed reductions in CRP after fish oil supplementation (37), the few studies in healthy individuals have showed no clear effect on serum CRP (38,39) and inconsistent results on plasma IL-6 (40,41). Also, Liou et al. (32) found no effects of a high (10E%) vs. low (4E%) LA intake on CRP or IL-6 in healthy men. In contrast with the promising findings in vitro (19), the evidence on the effect of (n-3) PUFA on soluble chemoattractants and adhesion molecules in healthy individuals is sparse and inconsistent (41–46) and some studies suggest that fish oil-induced reductions in VCAM-1 may occur in older subjects only (42,43). Moreover, soluble VCAM-1 levels are difficult to interpret, because they originate from molecules shed, for example, from endothelial cells and are thought to reflect a high expression on the cells, which may be an oversimplification. To our knowledge, the effects of fish oil on circulating MCP-1, oxLDL, and CD40L have not been investigated in healthy humans. The MCP-1 lowering in the OO+S/B group is difficult to explain and may be a LA effect or a chance finding. In a study among hypertensive subjects, fish oil increased the oxidizability of LDL (47), but plasma oxLDL did not differ in our study. Following an acute myocardial infarction, 300 patients were randomized to 4 g/d fish oil or corn oil for 1 y, resulting in decreased soluble CD40L, but in both groups (48). As reviewed by Vanschoonbek et al. (49), some studies have shown effects of (n-3) PUFA on various hemostatic factors. However, in line with our results, trials in healthy adults (35,50) and patients (51) have shown no effect of fish oil on blood fibrinogen levels or other hemostatic factors.
To our knowledge, we are also the first to investigate the effects of fish oil on soluble adiponectin in healthy, normal-weight humans. In rodents and obese humans, EPA increased serum adiponectin (52), an effect that has been inversely associated with the risk of CVD events (22). In an uncontrolled dietary intervention study, a concomitant increase in the intake of fish and rapeseed oil while avoiding (n-6) PUFA-rich oils also increased serum adiponectin (53). However, in our highly controlled and standardized setting, plasma adiponectin was not affected in healthy subjects.
Greater differences in the LA intake among the fat groups would have been desirable but would have required expensive, fully controlled diets with modified foodstuffs. We might have seen more profound changes in our risk markers with older, less healthy participants, but the focus of this study was early prevention. The choice of olive oil as the capsule placebo can be criticized, because, despite the reported neutral effects of monounsaturated fatty acids on plasma cholesterol (30), olive oil contains antiinflammatory compounds (54). However, we did not want to interfere with our dietary fat intervention by providing, for example, an (n-6) PUFA-rich oil as the placebo. Because no changes were seen in the OO groups during the intervention, the olive oil does not seem to have affected our results.
We conclude that 8 wk of fish oil supplementation lowers plasma TAG concentrations even in subjects with initially low plasma TAG. None of the other traditional or emerging markers of inflammation and CVD risk were affected, neither by fish oil alone nor in combination with varying background dietary LA intakes.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Author disclosures: C. T. Damsgaard, H. Frøkiær, A. D. Andersen and L. Lauritzen, no conflicts of interest.
5 Abbreviations used: BP, blood pressure; CD40L, cluster of differentiation antigen 40 ligand; CRP, C-reactive protein; CVD, cardiovascular disease; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; EPA, eicosapentaenoic acid, E%, percentage of energy intake; FO, fish oil capsule; HDL-C, HDL cholesterol; HOMA, homeostasis model assessment, HR, heart rate; IL, interleukin; LA, linoleic acid; LCPUFA, long-chain PUFA; LDL-C, LDL cholesterol; MCP-1, monocyte chemoattractant protein-1; OO, olive oil capsule; oxLDL, oxidized LDL; PBMC, peripheral blood mononuclear cell; R/K, low-LA fats; S/B, high-LA fats; TAG, triacylglycerol; TC, total cholesterol; VCAM-1, vascular cell adhesion molecule-1.
Manuscript received 4 December 2007. Initial review completed 9 January 2008. Revision accepted 13 March 2008.
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LITERATURE CITED |
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