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Nutrition and Disease

An Oil Mixture with Trans-10, Cis-12 Conjugated Linoleic Acid Increases Markers of Inflammation and in Vivo Lipid Peroxidation Compared with Cis-9, Trans-11 Conjugated Linoleic Acid in Postmenopausal Women^1,2

³ Department of Human Nutrition, Faculty of Life Science, University of Copenhagen, 1958 Frederiksberg, Denmark; ⁴ Biochemistry and Nutrition Group, BioCentrum, DTU, Technical University of Denmark, 2800 Lyngby, Denmark; ⁵ Clinical Nutrition and Metabolism, Department of Public Health Caring Science, Faculty of Medicine, Uppsala University, 75105 Uppsala, Sweden; and ⁶ Department of Endocrinology and Metabolism C, Aarhus University Hospital, 8000 Aarhus C, Denmark

^* To whom correspondence should be addressed. E-mail: tth{at}life.ku.dk.

	ABSTRACT

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
A mixture of trans-10, cis-12 (t10,c12) and cis-9, trans-11 (c9,t11) conjugated linoleic acid (CLA mixture) reduced atherosclerosis in animals, thus the effect of these isomers on endothelial dysfunctions leading to inflammation and atherosclerosis is of interest. We gave 75 healthy postmenopausal women a daily supplement of 5.5 g of oil rich in either CLA mixture, an oil rich in the naturally occurring c9,t11 CLA (CLA milk), respectively, or olive oil for 16 wk in a double-blind, randomized, parallel intervention study. We sampled blood and urine before and after the intervention. The ratios of total cholesterol:HDL cholesterol and concentrations of C-reactive protein, fibrinogen, and plasminogen activator inhibitor-1 were significantly higher in women supplemented with the CLA mixture than in those supplemented with CLA milk. Plasma triacylglycerol was significantly higher and HDL cholesterol was lower in women supplemented with the CLA mixture than with olive oil. Both CLA supplements increased lipid peroxidation, a marker of in vivo oxidative stress measured as urinary free 8-iso-prostaglandin F₂. However, the CLA mixture increased lipid peroxidation more than the CLA milk did. The plasma cytokines interleukin-6 and tumor necrosis factor- were not affected by the treatments, nor were any of the other variables measured. In conclusion, oil containing trans-10,cis-12 CLA has several adverse effects on classical and novel markers of coronary vascular disease, whereas the c9,t11 CLA isomer is more neutral, except for a small but significant increase in lipid peroxidation compared with olive oil.

	Introduction

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

Increased plasma concentration of the acute phase reactant C-reactive protein (CRP), a marker of inflammation (10,11), has been shown to be a strong predictor of cardiovascular disease (CVD) (12,13). t10,c12 CLA has been reported to increase plasma CRP compared with placebo, whereas the CLA mixture, as well as the 2 isomers tested separately, did not have such effects (14,15). Endothelial inflammation and CVD have also been associated with elevated plasma levels of interleukin-6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1), intermediary cell adhesion molecule-1 (ICAM-1) (16), and monocyte chemoattractant protein-1 (MCP-1) (17). As far as we know, only 1 study has examined the effect of CLA (the commercial mixture) on the VCAM-1 expression and this study found no effects compared with olive oil (18). The c9,t11 CLA isomer was demonstrated to decrease the ratio of total cholesterol:HDL cholesterol compared with the t10, c12 CLA isomer (19). However, other studies have not confirmed this opposing effect of the 2 bioactive CLA isomers (20,21).

Elevated fibrinogen, a coagulation factor and marker of inflammatory reaction (12,22,23), is strongly and independently associated with risk of CVD (24). A study in patients with type 2 diabetes has reported that a CLA mixture decreased plasma fibrinogen (25). The major regulator of fibrinolysis is plasminogen activator inhibitor type-1 (PAI-1) (26). High PAI-1 concentrations have been associated with CVD (27–30), obesity, and type 2 diabetes (31–33), and thereby with endothelial dysfunction and inflammation (34). The effect of a CLA mixture on PAI-1 has been investigated in a single study, but no effect was found (35). The same 2 CLA isomers were demonstrated to increase free radical-mediated lipid peroxidation, which has been suggested to be associated with decreased insulin sensitivity (36).

The aim of the present study was to compare the effects of 2 supplementations with different contents of CLA isomers on CVD risk markers (plasma lipids, inflammatory risk markers, and in vivo lipid peroxidation) in postmenopausal women, a risk group in regard to diabetes type 2 and thereby CVD (37,38). The effect of the CLA supplementations was compared with olive oil. Data on plasma insulin concentrations, BMI (kg/m²), body fat, and waist:hip ratio are reported elsewhere (M. Raff, T. Tholstrup, S. Toubro, J. M. Bruun, P. Lund, E. M. Straarup, R. Christensen, M. B. Sandberg, and S. Mandrup, unpublished data).

	Subjects and Methods

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
    Design. We performed a 16-wk double-blinded, randomized, parallel study with dietary supplementation rich in either a CLA mixture or c9,t11 CLA, the predominant CLA isomer in milk (CLA milk), or olive oil as control. The decision to include supplements instead of incorporation of CLA in natural foods was based on experience from a previous study in which incorporating CLA into the diet caused rapid oxidation. We provided the dietary supplements to the study participants at monthly visits to the Department of Human Nutrition, when they also returned leftover capsules. The participants were stratified according to blood pressure (BP), waist circumference, and smoking habits to 1 of the 3 dietary supplementations and we assessed all outcome variables at the start and the end of the intervention.

    Subjects. We recruited 75 postmenopausal women by advertising in local newspapers and by a list obtained from the Danish Central National Register. Baseline values did not differ among the 3 groups (Table 1). All women were apparently healthy as indicated by a medical and lifestyle questionnaire. Exclusion criteria were: BMI >35 kg/m², hypertension, chronic disease, regular use of medication, <1 y since last menstruation period. Smokers were equally divided in the 3 treatment groups. We instructed all participants to maintain the same level of physical activity throughout the study. They all agreed to refrain from donating blood 2 mo before and during the study and to refrain from taking dietary supplements and medication that might interfere with study measurements (e.g. acetylsalicylic acid). One or two weeks prior to the intervention, the participants completed a 3-d weighed food record on 2 weekdays and on 1 d the following weekend. All records were coded before being evaluated by a clinical dietician, who also calculated the energy intake and dietary composition using a national database (Dankost; National Food Agency, Søborg, Denmark). Habitual dietary intake did not differ among the 3 groups. Energy intake ranged from 4673 to 13,398 MJ/d (mean 8450 MJ) with 14.6–51.1% of energy (E %) from fat (mean 33.3 E %), 10.3–23.1% from protein (mean 16.2 E %), and 28.7–58.9% from carbohydrates (mean 45.8 E %). To ensure that the dietary intake of the participants did not change during the intervention, we asked the participants to repeat the weighed food record assessment during wk 8 of the intervention. All participants received a diary in which we instructed them to note all irregularities in their daily life and any untaken capsules. The protocol and aim of the study were fully explained to the participants (orally and in writing) before they gave their written informed consent. The Scientific Ethics Committee of the municipalities of Copenhagen and Frederiksberg (KF) 01–166/03 approved the research protocol.

    Sampling and analysis. After a 12-h overnight fast, a biotechnician collected venous blood before the intervention period and at the end of the study (after 16 wk).

    Blood lipids. We collected blood for lipoproteins and FA analyses in tubes containing EDTA kept on ice and centrifuged at 3000 x g for 15 min at 4°C. Plasma for fatty acid analyses was stored at –80°C and plasma for blood lipids at –20°C until the samples were analyzed. LDL and HDL cholesterol were assessed by enzymatic colorimetric procedure (LDL-C-plus and HDL-C-plus 2nd generation kit from ROCHE) on a Cobas Mira Plus Analyser (Roche Diagnostic). We assessed cholesterol and TAG concentrations in plasma by enzymatic procedures (CHOD-PAP and GPO-PAP, respectively; both kits from ROCHE Cholesterol) on a Cobas Mira plus analyzer (Roche Diagnostic).

    Inflammatory markers. We collected blood for high sensitive (hs) CRP, IL-6, tumor necrosis factor (TNF), and MCP-1 in dry tubes and after coagulation the samples were centrifuged at 1600 x g for 10 min at 4°C and stored at –20°C until analyzed. We measured the plasma CRP concentrations using a hs chemiluminescent immunometric assay, Immulite 1000 (Diagnostic Products). Intra-assay CV was 1.34% (n = 3). Plasma levels of IL-6, TNF, and MCP-1 were measured using specific hs human ELISA. The IL-6 assay (Quantikine HS600, R&D Systems Europe) had an intra-assay CV of 5.5% (n = 12). The TNF assay (Quantikine HSTA00C, R&D Systems Europe) had an intra-assay CV of 3.5% (n = 12). The MCP-1 assay (R&D Systems Europe) had an intra-assay CV of 8.1% (n = 12). Blood for analysis of adhesion molecules was collected in Na heparin tubes. The plasma concentration of the adhesion molecule serum VCAM-1 and ICAM-1 was determined using an ELISA kit (Human sVAM-1 Quantikine ELISA kit and Human sICAM-1 Paramiter ELISA kit; R&D Systems Europe). The analysis was performed on a SLT-Rain Bow from SLT-Labinstruments.

    Hemostatic risk markers. We collected blood for factor VII coagulant activity (FVII:c) and fibrinogen in citrated tubes (kept at room temperature for not more than 1 h) and centrifuged at 3000 x g for 20 min at 20°C. Plasma was pipetted into plastic vials, rapidly frozen, and stored at –80°C. Plasma FVII:c was assessed in a 1-stage clotting assay. After incubation of 50 µL diluted test plasma (1:10 in trihydroxymethylaminomethane-buffer) and 40 µL human FVII-deficient plasma and human thromboplastin (Thromborel S, Dade Behring), the clotting time was recorded on an ACL-300 (Instrumentation Laboratory SPA) and FVII:c expressed relative to an activity of 100 using a 3-point standard curve. Additional details have been described previously (39). Fibrinogen in the test sample was converted to fibrin by addition of purified bovine thrombin. The coagulation time was measured after addition of purified bovine thrombin, IL-Test-Fibrinogen-C, an automated clot assay (Instrumentation Laboratories), and the time required to form the clot was measured using an ACL 300 analyzer (ACL instrumentation Laboratorie SPA). The CV for this assay was 4.69% (n = 3) and 2.84% for the in house control (n = 24). Blood for PAI-1 antigen (ag) was collected in stabilyte tubes with citrate, which were immediately placed on ice and centrifuged at 3000 x g for 15 min at 4°C within 2 h of blood sampling and stored at –80°C until analysis. The concentration of PAI-1ag in plasma was analyzed by an enzymatic immunoassay (ELISA) procedure (Biopol TintElize PAI-1 kit) using a SLT Rainbow Scanner (SLT Labinstruments Ges. m.b.h., A5082). The intra assay CV was 4.08% (n = 12).

    F₂-isoprostane (free radical-mediated lipid peroxidation). The participants collected urine over 24 h before and after the intervention period. We recorded the volume and density and the samples were stored at –80°C until analysis for free 8-iso-prostaglandin (PG) F₂. Urine samples (50 µL) were analyzed for free 8-iso-PGF₂ using a specific and validated radioimmunoassay as described elsewhere (40). The cross-reactivities of the 8-iso-PGF₂ antibody with 15-keto-13, 14-dihydro-8-iso-PGF₂, 8-iso-PGF_2β, PGF₂, 15-keto-PGF₂, 15-keto-13,14-dihydro-PGF₂, thromboxane B2, 11β-PGF₂, 9β-PGF₂, and 8-iso-PGF₃, respectively, were 1.7, 9.8, 1.1, 0.01, 0.01, 0.1, 0.03, 1.8, and 0.6%. The detection limit of the assay was 23 pmol/L. The urinary concentrations of 8-iso-PGF₂ were adjusted to the total 24-h urine volume.

    Statistics. To compare the effects of the 3 diets, we used a mixed model ANCOVA and used the baseline values as covariates. We set the responses parameters as fixed effects and random effect was the participant ID number. We used the SAS statistical package (version 9.1, SAS Institute) for all our statistical analyses. When we detected significant treatment effects (P < 0.05), the Tukey-Kramer test was used for a post hoc pairwise comparison. When necessary, we logarithmically transformed values to normalize the distribution of residuals and to obtain variance homogeneity. Statistical tests were performed on the transformed data. Data describing the characteristics of the participants are summarized as means ± SD and data on outcome variables are expressed as least squares (LS) means ± SE, adjusted for baseline values and other variables if noted. We tested baseline BP (both systolic and diastolic), waist circumference, and smoking status for influence on the results, but these parameters were not included in the statistical model, because no effect was found. We determined the Pearson correlation coefficient from pair wise correlations of values (end – start values) from the total sample of women.

	Results

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
    Compliance. Eighty-one subjects were included in our study and 75 completed the 16-wk intervention. Three of the 6 drop-outs withdrew consent and 3 had nonsevere side effects. The drop-outs were distributed as follows: 2 in the CLA mix, 3 in the CLA milk group, and 1 in the control group. The length of the intervention period was 112 ± 3 d. Compliance, assessed by capsule counting, did not differ among the groups and was 98.2 ± 2.2%, 98.8 ± 1.9%, and 98.7 ± 1.4% in the CLA mixture, CLA milk, and control groups, respectively. The relative proportions (weight %) of the specific CLA isomers in the plasma CE reflected the dietary supplements after the intervention. Similar results were obtained for plasma TAG and phospholipids (data not shown).

    Dietary intake. The women in the CLA milk group reported a lower energy intake (7330 ± 310 kJ) during the intervention than those in the control (8100 ± 260 kJ; P = 0.02) and CLA mixture groups (8420 ± 320 kJ; P = 0.01). The fat intake in the CLA milk group (31.5 ± 1.0 E %) was also reported to be lower than the control group (34.2 ± 0.9 E %; P = 0.03) when expressed as E % but not when expressed as g/d. There were no other differences in dietary intake during the intervention. The energy and fat content (both changes and intake during the intervention) in the diet did not affect body composition and insulin sensitivity parameters. Furthermore, body weight and fat mass were not lower after the CLA milk supplement compared with after the other supplements (M. Raff, T. Tholstrup, S. Toubro, J. M. Bruun, P. Lund, E. M. Straarup, R. Christensen, M. B. Sandberg, and S. Mandrup, unpublished data).

    Plasma lipids. Women supplemented with the CLA mixture had an 11% higher ratio of plasma total cholesterol:HDL cholesterol than those supplemented with CLA milk (P < 0.05) (Table 3). Compared with the control group, women in the CLA mixture group had 14% lower HDL cholesterol concentration (P < 0.01), a 17% higher ratio of total cholesterol:HDL, and 15% higher plasma TAG (P < 0.01) (Table 3). Plasma LDL cholesterol concentrations did not differ among the 3 groups.

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View larger version (22K): [in this window] [in a new window]   FIGURE 1  Plasma concentrations of CRP (A), fibrinogen (B), and plasminogen activator inhibitor 1 (C) and urine 8-iso-PGF2 concentration (adjusted to 24 h volume) in postmenopausal women who received olive oil, CLA milk, or the CLA mixture daily for 16 wk. Values are LS means ± SEM, adjusted for baseline levels, n = 18–24. Means without a common letter differ, P < 0.05 (mixed model ANCOVA).

	Discussion

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

We found greater free radical-mediated lipid peroxidation in women supplemented with the CLA mixture compared with those given the CLA milk isomer and control, and it was greater in lipid peroxidation than in the control subjects. These observations are in agreement with results from other studies in which t10,c12-CLA (14) and the c9,t11 isomer increased levels of 8-iso-PGF₂ in humans (53). Increased production of reactive oxygen species is suggested to be one of the mechanisms underlying endothelial dysfunction and lipid peroxidation (54) and growing evidence indicates that reactive oxygen species are involved in the development of CVD (55). It is still unknown whether CLA-induced lipid peroxidation is proatherogenic in humans. However, it has been suggested that lipid peroxidation may decrease insulin sensitivity (36) and thereby lead to diabetes-associated CVD (56). CLA-induced lipid peroxidation might mediate insulin resistance by impairing cellular insulin signaling due to increased radical generation (57,58). The existence of this mechanism is supported by our observation of a correlation between F₂-isoprostanes and PAI-1, which is known to be associated with insulin sensitivity (30). This, together with the observed strong association with plasma CRP, might have consequences for inflammation and, therefore, for risk markers of CVD (59).

In this study, women given the CLA mixture had a lower plasma HDL cholesterol concentration and higher ratio of total cholesterol:HDL cholesterol than the CLA milk and the olive oil control. In addition, an increase in plasma TAG concentration with a concomitant decrease in HDL cholesterol, probably due to increased CE transfer protein, occurred after the CLA mixture compared with control. A lower HDL cholesterol concentration after a mixture containing t10,c12 CLA is in agreement with studies by others (19,20). However, the lower plasma HDL cholesterol concentration after t10,c12 CLA does not agree with findings by others showing either no effect (60) or a higher plasma HDL cholesterol after intake of a mixture of CLA found in type 2 diabetic patients (25). Overall, the effects of the CLA isomers on blood lipids are not pronounced nor are they fully in agreement. This may be partly due to the diverse characteristics of participants in different studies including healthy, obese, or diabetic individuals. We also found HDL cholesterol to be strongly and negatively related to CRP, as reported by others (61). The inverse association between HDL cholesterol and inflammation is interesting, because the role of HDL has not been fully elucidated and supports the idea that HDL cholesterol may cause or is associated with factors that protect against inflammation. Whether the specific changes in parameters after the intervention found in this study are of clinical importance is somewhat uncertain, because most of the risk markers are new. Chronically increased inflammation is a risk for development of atherosclerosis (11) and there is a trend in the present study toward a mixture containing t10,c12 CLA having some adverse effects on several biochemical parameters that are involved in CVD, whereas the c9,t11 CLA isomer appears more neutral. The overall pattern of clustering associations between risk markers in this study may be more meaningful than small changes in individual markers. A disadvantage of our study was the somewhat lower energy intake in the CLA milk group. However, body weight and body fat mass did not change in this group compared with baseline or the control group.

In conclusion, unlike the c9,t11 CLA isomer, which occurs naturally, a CLA mixture containing t10,c12 decreased HDL cholesterol and raised plasma TAG, together with several inflammatory markers. Both CLA supplementations increased in vivo lipid peroxidation, with the mixture containing t10,c12 CLA having more pronounced effects than the c9,t11 CLA isomer. Overall, our results confirm that the mixture with t10,c12 CLA has a cluster of adverse effects on CVD markers, whereas c9,t11 CLA isomer appears to be more neutral.

	ACKNOWLEDGMENTS

 
We thank our technicians, Ella Jessen and Hanne Lysdal Petersen, from the Department of Human Nutrition and Grete Peitersen from the Danish Technical University for technical assistance. We thank Pernille Nonboe for analysis of adhesion molecules.

	FOOTNOTES

 
¹ Supported by the Danish Dairy Research Foundation and The Danish Research Development Program for Food Technology (Foetek).

² Author disclosures: T. Tholstrup, M. Raff, E. M. Straarup, P. Lund, S. Basu, and J. M. Bruun, no conflicts of interest.

⁷ Abbreviations used: ag, antigen; BP, blood pressure; c9,t11, cis-9,trans-11; CE, cholesterol ester; CLA, conjugated linoleic acid; CLA milk, c9,t11 CLA; CLA mixture, mixture of trans-10,cis-12 and cis-9,trans-11; CRP, C-reactive protein; CVD, cardiovascular disease; E %, percent of energy; hs, high sensitive; FVII:c, factor VII coagulant activity; ICAM-1, intermediary cell adhesion molecule-1; IL-6, interleukin-6; LS, least squares; MCP-1, monocyte chemoattractant protein-1; PAI-1, plasminogen activator inhibitor type-1; PG, prostaglandin; t10,c12, trans-10,cis-12; TAG, triacylglycerol; TNF, tumor necrosis factor; VCAM-1, vascular cell adhesion molecule-1.

Manuscript received 25 March 2008. Initial review completed 5 May 2008. Revision accepted 29 May 2008.

	LITERATURE CITED

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 

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