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© 2006 American Society for Nutrition J. Nutr. 136:2844-2848, November 2006

Nutrition and Disease

Flaxseed Oil Supplementation Does Not Affect Plasma Lipoprotein Concentration or Particle Size in Human Subjects1

Charles R. Harper2,*, Megan C. Edwards3 and Terry A. Jacobson2,4

2 Department of Medicine, Emory University, Atlanta, GA 30303; 3 Virginia Commonwealth University, Richmond, VA 23284; and 4 Office of Health Promotion and Disease Prevention, Atlanta, GA 30303

* To whom correspondence should be addressed. E-mail: charper{at}emory.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Material and Methods
 Results
 Discussion
 LITERATURE CITED
 
{alpha}-Linolenic acid (ALA) is a major dietary (n-3) fatty acid. Some clinical trials with ALA supplementation have shown reduced cardiovascular risk; however the specific cardioprotective mechanism is not known. We studied the effects of daily supplementation with ALA derived from flaxseed oil on concentrations of plasma LDL cholesterol, HDL cholesterol, intermediate density lipoprotein cholesterol, and lipid particle sizes. In a randomized double-blind trial, 56 participants were given 3 g/d of ALA from flaxseed oil in capsules (n = 31) or olive oil containing placebo capsules (n = 25) for 26 wk. Changes in plasma HDL cholesterol, LDL cholesterol, and triglyceride concentrations did not differ between the 2 groups at 26 wk. The adjusted plasma total cholesterol concentration at 26 wk was 0.45 mmol/L higher in the flaxseed oil group (5.43 ± 0.03 mmol/L) compared with the olive oil group (5.17 ± 0.07 mmol/L) (P = 0.026). ALA did not affect LDL, HDL, or IDL particle size; however, the concentrations of the large, less atherogenic LDL1 (P = 0.058) and LDL2 (P = 0.083) subfractions tended to be greater in the ALA group. In conclusion, ALA does not decrease CVD risk by altering lipoprotein particle size or plasma lipoprotein concentrations.


   Introduction
TOP
 ABSTRACT
 Introduction
Material and Methods
 Results
 Discussion
 LITERATURE CITED
 
Evidence from several epidemiologic studies suggests that {alpha}-linolenic acid may provide a substantial cardioprotective effect (1–3). The mechanism whereby (n-3) fatty acids exert this cardioprotective effect has not been established. Several studies have tested the effect of (n-3) fatty acids on intermediate markers of cardiovascular disease (4–6). One such intermediate marker is lipoprotein particle size. Although LDL-cholesterol concentration, not the particle size, remains the primary target of therapy for the prevention of coronary heart disease (CHD),5 increasing research has been devoted to the study of the heterogeneity of LDL particles. Smaller diameter and denser LDL particles are known to have a greater proclivity for oxidation and an enhanced ability to penetrate the intima than larger, less dense LDL particles. Smaller, denser LDL particles are associated with an increased risk for CHD in prospective studies. HDL cholesterol particles are also heterogeneous and evidence suggests that larger diameter HDL particles may be more cardioprotective (7). Some small studies with marine-based fish oil in patients with normal to mildly elevated triglycerides suggest that marine-based (n-3) polyunsaturated fatty acids (PUFA) may have little effect on LDL particle size and a beneficial effect on HDL subfractions (8–11); however, the effect that plant-based (n-3) PUFA ({alpha}-linolenic acid) has on lipoprotein particle size has not been widely characterized.

In the FORCE trial (flaxseed oil to reduce intermediate cardiac endpoints) we utilized a randomized placebo-controlled study design to analyze the effect that a 3-g daily supplement of {alpha}-linolenic acid (ALA), in the form of flaxseed oil capsules, had on plasma lipoprotein subfractions vs. an olive oil placebo. The study population was predominantly African American patients with multiple chronic diseases.


   Material and Methods
TOP
 ABSTRACT
 Introduction
 Material and Methods
Results
 Discussion
 LITERATURE CITED
 
    Subjects. A total of 56 patients (49 women, 7 men) were enrolled in the study. Patients without known coronary heart disease were recruited predominantly from an academic general medicine clinic affiliated with a large urban public hospital. Participants were screened and excluded if they reported taking multivitamins, antioxidants, and fish oil or n-3 fatty acid supplements. Women of child-bearing age not using contraception or those who consumed >2 servings of fish/wk were also excluded. The full details of the study design has been previously described (12).

The experimental protocol was reviewed and approved by the Institutional Review Board at Emory University and the Grady Research Oversight Committee. Informed consent was obtained from each subject before the start of the study.

    Experimental design. Potential participants were evaluated during an initial screening visit that included a review of the eligibility and exclusion criteria. Participants that met eligibility criteria were scheduled for 2 run-in visits at 8 and 4 wk prior to randomization. All study visits took place in the Emory General Clinical Research Center. During these run-in visits, the research dietician instructed the participants on an AHA step-I diet. Participants were taught how to complete a 3-d food diary, and the records were analyzed for compliance with the diet using a standard food-record rating procedure (Nutritionist V). After 8 wk of following the AHA diet, participants were randomized to either a treatment group that was given 3 g of ALA (5.2 g of flaxseed oil) per day in the form of flaxseed oil capsules (Rx Vitamins) or a control group that was given 5.2 g of olive oil per day in the form of olive oil capsules (Oleomed) (Table 1). The 3-g dose of ALA was selected because it is the maximal dose generally regarded as safe (GRAS) by the FDA. The study biostatistician developed the randomization procedure. A randomization list was prepared using computer-generated random numbers. Random permuted blocks (size 2 or 4) were used to help ensure balance between the number of patients assigned to each treatment. The randomization scheme was provided to the data manager as a set of 60 sealed, sequenced, opaque envelopes containing the treatment assignment. As a patient entered the trial, the patient was assigned the next envelope in the sequence.


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  		TABLE 1 Fatty acid composition of flaxseed oil and olive oil capsules

 
At the randomization visit, baseline plasma lipoprotein levels were measured and dietary diaries were collected. Participants returned for visits at 12 and 26 wk and were instructed to fast for 12 h prior to each visit for laboratory work. During these visits, plasma lipoprotein levels were measured and pill counts were obtained to monitor compliance. The research dietician reinforced the AHA step-I diet throughout the study and analyzed patient 3-d food diaries. Medication compliance was assessed by both pill count and by patient self-reports throughout the study. A priori, noncompliance with therapy was defined as consuming <80% of medications by pill count or by self-report.

    Blood collection and analytic methods. Blood samples were collected into 6 mL lavender-top EDTA glass tubes (Vacutainer Tube, Becton Dickinson). The tubes were inverted 10 times and then centrifuged at 600 x g for 10 min. Three mL of plasma was pipetted into a transfer tube and stored in a –70°C freezer until the end of the study, when all samples were analyzed at the same time. Plasma lipids were measured utilizing nonequilibrium density gradient ultracentrifugation to separate lipoproteins; ultracentrifugal separation was followed by enzymatic determination of cholesterol in all lipoprotein fractions with 400 sequential spectrophotometric measurements per sample. The final stage of analysis employs proprietary deconvolution software to determine subfractions of HDL, LDL, intermediate density lipoprotein (IDL) and VLDL. All lipid testing was performed at Atherotech, a CDC National Heart, Lung, Blood Institute standardized cholesterol testing laboratory, and the methodology was previously described (13).

    Statistical analysis. Statistical analyses were performed using SAS 6.12 software. Plasma lipoproteins were measured 4 wk prior to study randomization, at baseline, and at 12 and 26 wk. Baseline plasma lipoproteins concentrations were determined by averaging the measured plasma lipoprotein concentrations 4 wk prior to randomization with those obtained at randomization (wk 0) to minimize subject variability. Differences in plasma lipoprotein concentrations between groups were compared. Continuous variables were analyzed by the Student's t test to determine the difference between groups. The relative risks and 95% CI of dichotomous variables, such as gender, smoking status, diabetes, CHD, and hypertension, were calculated using Cochran-Mantel-Haenszel statistics. The plasma lipoprotein data were analyzed by linear mixed effects models for repeated measures data. Each variable was modeled as a function of treatment group (flaxseed vs. olive oil), time (baseline, 12 wk, 26 wk), the interaction between treatment group and time, and as covariates of gender and weight, where weight varied across time. In all cases, 2-sided tests were performed and significance level was determined at P < 0.05.


   Results
TOP
 ABSTRACT
 Introduction
 Material and Methods
 Results
Discussion
 LITERATURE CITED
 
    Subjects and diet. Twenty seven of 31 subjects randomized to flaxseed oil and 22 of 25 subjects randomized to olive oil successfully completed the trial and were included in the final analysis. Of 7 patients excluded, 1 participant was excluded after records indicated consumption of >4 fish meals per week. Six other participants were excluded from the final analysis because of low compliance rates. The patients excluded and the remainder of the cohort did not differ in terms of demographics or baseline plasma lipoproteins. During the study, only 5 participants reported any symptoms that were related to the fatty acid supplements, and both flaxseed and olive oil capsules were well tolerated. Symptoms were minimal and included dry mouth (3%), change in bowel habits (3%), and dyspepsia (3%). Randomization was successful in that there were no significant differences between the groups at baseline (Table 2).


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  		TABLE 2 Baseline characteristics of study participants1

 
Participants were predominantly African American (80%) females (87%) with a mean age of 51 y. Participants had multiple chronic illnesses including hypertension (55%) and Type II diabetes (12%). Most participants were overweight or obese with a mean BMI of 37.4. Of the participants, 53.7% were on antihypertensive medicines, 26% were on daily aspirin, and 24% were on a HMG-CoA reductase inhibitor.

Compliance with the AHA step-1 diet was monitored from 3-d food records obtained 4 wk prior to randomization and at 0, 12, and 26 wk. The total energy intake and the percentage of energy obtained from fat, protein, carbohydrate, and alcohol was the same in the groups at baseline (Table 3) and remained the same at follow-up dietary assessment (data not shown). Despite pretrial education on an AHA step-1 diet, participants dietary patterns at wk 0 reflected high amounts of total fat (32% of total energy) and saturated fat (15% of total energy). Body weights did not change in either group and did not differ between groups through wk 26.


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  		TABLE 3 Nutritional intake of participants at baseline1

 
    Plasma lipoproteins. The ALA supplement produced an increase in the plasma total cholesterol concentration at 26 wk (Table 4), when adjusted for gender and weight (+0.45 mmol/L, P = 0.026), whereas this concentration did not change in the olive oil placebo. The LDL cholesterol, HDL cholesterol, IDL cholesterol, and triglyceride concentrations did not change over time or differ between the flaxseed and olive oil groups.


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  		TABLE 4 Plasma lipoprotein and lipoprotein subfraction concentrations in olive oil and flaxseed oil treated groups1

 
    Lipoprotein particle size. When using the vertical ultracentrifugation technique, the larger, less dense, and less atherogenic LDL subfractions are denoted as LDL1 and LDL2, and the smaller, denser, more atherogenic subfractions are referred to as LDL3 and LDL4. When measuring HDL, the larger, less dense, and more cardioprotective subfraction is denoted HDL2, whereas the smaller, denser, less cardioprotective subfraction is referred to as HDL3. ALA supplementation did not affect LDL, HDL, or IDL particle sizes compared with the olive oil placebo; however, there was a trend for an increase in the larger less atherogenic LDL1 (P = 0.058) and LDL2 (P = 0.083) subfractions.


   Discussion
TOP
 ABSTRACT
 Introduction
 Material and Methods
 Results
 Discussion
LITERATURE CITED
 
The majority of studies with whole or ground flaxseed suggest that flaxseed doses of 15–50 g/d cause a small to modest reduction in LDL cholesterol (8–15%) without a change in HDL cholesterol. These studies have been performed in both hypercholesterolemic and normocholesterolemic populations (14–17). In a recent randomized, controlled, 3-diet, 3-period, crossover study, 23 hypercholesterolemic patients consumed a series of 3 diets, including a high ALA diet that provided 6.5% of energy from ALA rich walnuts and walnut oil, a high linoleic acid diet, and a control diet resembling the average American diet with only 0.8% of energy from ALA. The LDL cholesterol levels in subjects consuming the ALA diet were decreased by 10% (P = 0.05) compared with controls (18). In contrast to whole or ground flaxseed, the majority of studies with flaxseed oil have failed to show any significant effect on lipids (11,19). This has led to speculation that the lignans in the flaxseed or insoluble fiber may be responsible for the cholesterol-lowering effect. Synthetic lignans, but not flax-related lignans, have significantly reduced LDL cholesterol (20).

The results of the Lyon Diet Heart Study using ALA enriched margarine do not support lipid-lowering as a possible cardioprotective mechanism. In this study, over 600 patients postmyocardial infarction (MI) were randomized to an ALA-enriched margarine resulting in a 73% reduction in cardiac death and nonfatal MI (risk ratio 0.27; 95% CI 0.12–0.69, P = 0.001) without changes in total plasma lipids (21).This trial was limited by multiple changes made in the diet of the treatment group compared with the control group, including a decrease in total energy and saturated fat, along with an increase in consumption of monounsaturated fat.

Although there are a few studies on the effect marine-based (n-3) fatty acids have on particle size in patients, the plant-based (n-3) fatty acid, ALA, has not been widely studied. Marine-based (n-3) fatty acids have been shown in some studies to increase the larger, more buoyant subfraction HDL2. In one study of patients with familial combined hyperlipidemia, the consumption of 4 fish oil capsules per day [3.4 g/d eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] resulted in a 40% increase in plasma HDL2 without a significant change in total HDL cholesterol (9). The results of studies on the effect of marine-based (n-3) fatty acids on LDL subfractions and particle size have been mixed. In one study evaluating LDL cholesterol particle size, 14 patients with familial combined hyperlipidemia were given 3.4 g of EPA + DHA/d from fish oil, resulting in a significant increase in LDL1 and LDL2, the larger less atherogenic LDL subfractions (22), whereas other studies have not demonstrated any change in LDL particle size (10,11). The divergent study results may reflect populations studied with different types of hyperlipidemia. In studies using populations with higher triglycerides, the shift in LDL particle size is more evident.

Marine-based (n-3) fatty acids modulate lipoprotein particle size by acting as agonists for the peroxisome proliferator-activated receptor (PPAR) complex. In studies by De Caterina and Massoro (23), nutritionally relevant concentrations of (n-3) polyunsaturated fatty acids have been shown to activate PPAR-{alpha}, resulting in the decreased activation of the nuclear factor-{kappa}B system of transcription factors, and this effect, although present with ALA, is more pronounced in fatty acids with more double bonds, such as EPA and DHA. Whether ALA has properties similar to marine-based (n-3) polyunsaturated fatty acids (EPA and DHA), resulting in favorable changes in lipoprotein particle size has not been clearly demonstrated. In a study involving dietary supplementation with ALA-rich walnuts, the total plasma lipids were not altered; however, the amount of cholesterol in the small LDL subfraction was decreased (24). This study is limited by the fact that walnuts are a rich source of (n-6) fatty acids and other micronutrients that may affect particle size.

In the FORCE trial, flaxseed oil did not affect lipoprotein particle size or plasma lipoprotein levels (Table 4). There was an unexpected increase in total cholesterol (P = 0.026) in the flaxseed oil group compared with the olive oil group at 26 wk. We were unable to find prior reports of this in the literature. The increase in total cholesterol might have resulted from the increase in the less atherogenic LDL subfractions (LDL1, LDL2). There was also a trend at 26 wk for an increase in the larger, less atherogenic LDL subfractions, LDL1 (P = 0.058) and LDL2 (P = 0.083), in the flaxseed oil group compared with the olive oil group. This is consistent with the activity of other PPAR{alpha} activators including fibric acid derivatives, which have been shown to increase the concentrations of large less atherogenic LDL subfractions (25).

The FORCE trial was limited by the fact that patients in the study consumed high levels of saturated fat (10% total energy), which has been shown to increase LDL particle size and may mask any effect produced by ALA. Exercise has also been shown to reduce HDL particle size and exercise habits were not recorded in this study. Another limitation may have been the use of an olive oil placebo; although this is the standard in studies designed to test the conversion of ALA to EPA, olive oil has been shown to have an effect on lipoprotein metabolism and may have masked a beneficial effect of the flaxseed oil supplement (26). Finally, ~25% of participants were taking a statin. This class of drugs has been shown to modify particle size and may have masked any changes in particle size caused by ALA; however, subgroup lipid analysis did not suggest a differential effect due to statins (27).

In summary, the findings from the FORCE trial suggest that if any cardioprotection is derived from ALA or flaxseed oil, it is not mediated by improvement in lipids or lipoprotein particle size. It remains an open question if ALA itself has intrinsic cardioprotective benefit or if the in vivo conversions of ALA to EPA or DHA, which are known cardioprotective fatty acids, are responsible for the cardiac benefit seen in observational and clinic trials with ALA. More research is needed to clarify the mechanism for the cardioprotective effects of ALA.


   ACKNOWLEDGMENTS
 
We thank Mrs. Betty Webb for her help in preparing this manuscript.


   FOOTNOTES
 
1 Supported in part by a grant (M01-RR00039) from the Emory University General Clinical Research Center (Grady Health System) and by a grant from the Emory Medical Care Foundation. Back

5 Abbreviations used: ALA, {alpha}-linolenic acid; CHD, coronary heart disease; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FORCE, flax seed oil to reduce intermediate cardiac endpoints; IDL, intermediate density lipoprotein. Back

Manuscript received 9 May 2006. Initial review completed 10 June 2006. Revision accepted 22 August 2006.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Material and Methods
 Results
 Discussion
 LITERATURE CITED
 

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