© 1997 American Heart Association, Inc.
Articles |
Plasma Lipoprotein (a) Levels in Men and Women Consuming Diets Enriched in Saturated, Cis-, or Trans-Monounsaturated Fatty Acids
From the Diet and Human Performance Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, USDA (B.A.C., J.T.-J., M.E.S.), Beltsville, MD; Lipid Metabolism Laboratory, the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University (E.J.S., J.L.-J., A.H.L.), Boston, MA; The Lipid Research Clinic (R.A.M.), The George Washington University Medical Center, Washington, DC; and Statistics Collaborative (J.W.), Washington, DC.
Correspondence to Beverly A. Clevidence, PhD, Diet and Human Performance Laboratory, Beltsville Human Nutrition Research Center, Building 308, Room 115, BARC-East, 10300 Baltimore Avenue, Beltsville, MD 20705-2350. E-mail Bev{at}bhnrc.arsusda.gov
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Abstract Studies that have shown adverse effects of trans-unsaturated fatty acids on plasma lipoprotein (a) [Lp(a)] levels have used levels of trans-fatty acid that are higher than those in the average U.S. diet. This study was conducted to clarify the effects on Lp(a) of trans-fatty acids levels commonly found in U.S. diets. Lp(a) levels were measured in a double-blind study of 29 men and 29 women who ate 4 controlled diets in random order for 6 weeks each. Fatty acids represented 39% to 40% of energy. The diets were: (1) Oleic (16.7% of energy as oleic acid); (2) Moderate trans (3.8% of energy as trans-monoenes, approximately the trans content of the U.S. diet); (3) High trans (6.6% of energy as trans-monoenes); (4) Saturated (16.2% of energy as lauric plus myristic plus palmitic acids). The Saturated diet lowered Lp(a) levels significantly (by 8% to 11%). Compared to the Oleic diet, the trans diets had no adverse effect on Lp(a) levels when all subjects were considered collectively. A subset with initially high levels of Lp(a) (
30 mg/dL), however, responded to
the High trans diet with a slight (5%) increase in Lp(a)
levels relative to the Oleic and Moderate trans diets. Thus,
in amounts commonly found in the typical U.S. diet, saturated fatty
acids consistently decrease Lp(a) concentrations. The adverse
effects of replacing cis- with trans-fatty acids
are only suggestive and are restricted to high trans intakes
in subjects with high Lp(a) levels.
Key Words: lipoprotein (a) • human diet • trans-fatty acids • hydrogenated fat • saturated fat • dietary fatty acids • monounsaturated fat • elaidic acid
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Lipoprotein (a), a low-density lipoprotein (LDL) particle linked to apoprotein (a) [apo(a)], may be an independent risk factor for developing coronary heart disease.1 2 3 4 5 Although the role of Lp(a) in promoting heart disease has not been definitively elucidated, the particle has both atherogenic and thrombotic potentials. Moreover, it has been reported to be considerably more atherogenic than LDL.5
Lipoprotein (a) levels are thought to be largely controlled by genetic factors.6 However, several reports have indicated that the type of fat consumed can alter Lp(a) levels.7 8 9 10 11 The possibility of modulating Lp(a) levels by dietary means is intriguing because effective pharmacological treatments for lowering Lp(a) concentrations are limited.12
Trans-unsaturated fatty acids, produced largely during the partial hydrogenation of vegetable oils, have been implicated in raising Lp(a) plasma levels.9 10 However, this finding has not been consistent among studies.10 13 These discrepancies may be due to variation in dietary design, length of feeding, characteristics of study subjects, or the amounts or isomeric compositions of the trans-fatty acids used. Reports from recent human feeding trials agree that trans- and cis-fatty acids have different metabolic effects on plasma LDL and possibly on high-density lipoprotein (HDL), and that trans- unsaturates adversely affect lipoprotein profiles.10 13 14 15 16 17 If at levels of intake characteristic of the U.S. diet trans-monounsaturates are consistently demonstrated to have the additional adverse effect of elevating Lp(a) levels, the need to reduce trans-fatty acids in the U.S. food supply would be accentuated.
We measured Lp(a) levels from plasma samples collected during a study that investigated the response of blood lipids to trans-fatty acid consumption.17 The objective of the present investigation was to compare plasma Lp(a) levels that result from consuming diets containing trans-unsaturated fatty acids within the range typically consumed in the U.S. diet on cis-monounsaturated fatty acids (oleic) and "cholesterol-raising" saturated fatty acids (lauric, myristic, and palmitic acids).
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Subjects
The subjects, healthy adults (29 men, 29 women) with a mean age of 43 years (range, 25 to 65 years), were free of metabolic disorders, including obesity, diabetes, gout, endocrine disorders, or liver and kidney disease. Recruitment details have been reported.17 Inclusion criteria required that volunteers have (1) plasma cholesterol levels between the 50th and the 75th percentiles for the sex and age of the volunteers screened; (2) HDL cholesterol levels above 0.91 mmol/L (35 mg/dL) for men and 1.03 mmol/L (40 mg/dL) for women; and (3) triglyceride levels under 3.39 mmol/L (300 mg/dL).
Subjects included 12 African Americans (7 men and 5 women), 7 smokers, and 7 women on steroidal hormones (2 on oral contraceptives; 5 on hormone replacement). The type and dosage of hormones did not change over the course of the study as assessed from daily records of prescription and nonprescription medication. Procedures for research with human volunteers were approved by the Institutional Review Board, Georgetown University School of Medicine.
Experimental Diets and Design
Four diets enriched in fatty acids—oleic (Oleic), moderate
trans (Mod Trans), high trans (High
Trans), and saturated (Sat)—were fed in a Latin square
design (6-week periods) so that each subject consumed all 4 diets.
Subjects were blind to dietary treatments. A previous report describes
the diets and their formulation and analyzed nutrient values
and procedures for blinding.17
Each diet contained 39% to 40% of energy as fatty acids (Table 1
). The Sat diet contained 16% of energy
as cholesterol-raising saturated fatty acids
(lauric+myristic+palmitic) and 11% of energy as oleic acid. To
formulate the Oleic, Mod Trans, and High Trans
diets, the Sat diet was modified by replacing 6% of energy from
saturated fat (lauric+myristic+palmitic) with an equal amount of either
oleic acid (Oleic diet), a combination of oleic and
trans-fatty acids (Mod Trans diet), or
trans-fatty acids (High Trans diet). The Oleic,
Mod Trans, and High Trans diets provided 17% to
18% of energy as monounsaturates (oleic or
oleic+trans-fatty acids). Naturally occurring
trans-isomers from meat, dairy products, and other foods
represented about 0.7% of energy in all diets. The levels
of stearic acid, which, unlike other common saturated fatty acids is
not hypercholesterolemic,18 19 20 were held
constant across diets at 3% of energy. Cholesterol levels
were held constant at approximately 0.083 mmol/MJ (13.5
mg/100 kcal) or about 400 mg/d at the average energy
level. Dietary fiber intake was 22 g/d to 25 g/d at an
energy intake of 11.72 MJ.
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Meals were prepared at the Human Studies Facility, Beltsville Human Nutrition Research Center, using a 14-day menu cycle. Trans-fatty acids were incorporated into margarines, baked goods, dips, gravies, and other foods using partially hydrogenated fats typical of those found in the U.S. food supply. Coconut oil, high oleic sunflower oil, and high linoleic safflower oil also were used to achieve the desired fatty acid compositions of the diets. The test fats were provided by member companies of the Institute of Shortening and Edible Oils (Washington, DC). Foods were weighed in direct proportion to caloric requirements. Subjects ate breakfast and dinner meals under supervision, Monday through Friday, at the dining facility. Lunch and weekend meals were packed for off-site consumption. Subjects agreed to eat all of the food and only the food provided by the study. Alcohol consumption was not allowed. Body weights were recorded before breakfast, Monday through Friday, and caloric intake was adjusted, as necessary, to maintain body weights within a range of ±1 kg.
Each of the 4 diets was composited and analyzed 6 times at the 11.72-MJ level and once at the 7.53-MJ level. Proximate analysis of protein, fat and carbohydrate,21 and total dietary fiber22 was performed by Hazelton Laboratories (Madison, WI). Levels of trans-fatty acids were measured by infrared spectroscopy;23 cis- and trans-positional isomers were determined by gas chromatography.24 Trans 18:1 monounsaturated fatty acids comprised 98% or more of the total dietary trans-fatty acids.
Lipoprotein Assays
Blood was collected from fasting subjects (12-h fast) prior to
breakfast (between 6 AM and 8:30 AM) with
replicates taken on Monday and Wednesday, or Tuesday and Thursday,
during the 6th week of each feeding period. In addition, baseline
samples were collected twice the week before controlled feeding
started. Procedures used for blood sampling and processing are those
described in the protocol for the Lipid Research Clinics
program.25 Blood was collected in tubes containing 1.5
mg/mL Na2 EDTA (final concentration) promptly cooled
on wet ice, and plasma was separated by low-speed
centrifugation (1400xg) for 20 minutes at
4°C. Plasma samples were coded to blind analysts to subject
treatments. The method of Gidez et al.26 was used to
isolate HDL. The triglyceride and cholesterol
contents of plasma and the HDL fractions were determined enzymatically
(Sigma Chemical Co., St. Louis, MO). Concentrations of LDL
cholesterol were calculated by the method of Friedewald et
al.27 A detailed description of the methodology for
determinations of lipoproteins other than Lp(a) has been
reported.17
Samples for Lp(a) analysis were frozen at -90°C. After the study was completed, samples were shipped on dry ice to the Lipid Metabolism Laboratory of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University for analysis. Levels of Lp(a) were measured as described previously3 13 25 with a commercially available enzyme-linked immunosorbent assay (Strategic Diagnostics, Newark, DE). Briefly, diluted samples (1:201) were incubated for 1 hour in microtiter strip wells coated with a monoclonal anti-Lp(a) antibody that does not cross-react with plasminogen. After 4 washes, a 20-minute incubation with a polyclonal anti-Lp(a) horseradish peroxidase conjugate was followed by another 4 washes. An incubation of substrate (hydrogen peroxide) and chromogen (O-phenylenediamine) was stopped after 20 minutes by the addition of 2 N sulfuric acid. The absorbance was read at 492 nm with a Dynatech MR 600 microtiter plate reader (Dynatech Inc., Vienna, VA). The Lp(a) values were calculated from the standard curve generated from the set of standards provided with each plate. Intraassay and interassay coefficients of variation were 3.2% and 5.2%, respectively. All samples from an individual subject were included in a single run.
Statistical Analysis
Values for Lp(a) were the average of the replicate
determinations taken on 2 days during the final week of the feeding
periods. Both logarithmic- and square-root transformations were
conducted to normalize Lp(a) data. Statistical analyses were
determined on both the original and transformed data. The reported data
are arithmetic means. Data were analyzed by analysis of
variance (ANOVA) for main effects and interactions of gender, diet, and
period using SAS version 6.06 (SAS Institute, Cary, NC).
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Results |
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As commonly reported for this lipoprotein, Lp(a) values were skewed; a high proportion of values fell at the lower end of the range. The transformed data had approximate normal distributions. Transformed and untransformed data produced essentially the same results, but the fit of the model was better for the raw than for the transformed data. Thus Lp(a) values are given as original, rather than transformed, data.
Baseline
Baseline levels of Lp(a) and other plasma lipoproteins are
reported in Table 2. Levels of Lp(a)
ranged from 0.5 mg/dL to 111 mg/dL. No difference in
Lp(a) values due to gender was detected at baseline. African Americans
had higher levels of Lp(a) (32.0±8.9 mg/dL) than whites
(22.9±3.4 mg/dL); however, the differences were not
statistically significant. It should be noted that the statistical test
for difference by race has low power because of the small number of
African Americans. There were no significant correlations of Lp(a)
levels with total, LDL, or HDL cholesterol levels.
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Response to Diet
Because the Lp(a) values of men and women did not differ in
response to diet, the data were pooled across gender. When the 58
subjects were considered collectively, the Sat diet produced Lp(a)
levels that were 8% to 11% lower than levels produced by the other
diets; these differences were statistically significant (Table 3). By contrast, when all subjects were
considered collectively, there were no statistically significant
differences among Lp(a) levels produced by consumption of the Oleic,
Mod Trans, or High Trans diets.
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The Lp(a) data were grouped into 3 strata according to baseline Lp(a)
levels: low (
5 mg/L), medium (>5 mg/dL but <30
mg/L), high (30 mg/L). The cutoff of 30 mg/L was
chosen because values at this level and above28 29 30 have
been associated with increased risk of coronary artery disease.
The cutoff level of 5 mg/L was chosen arbitrarily. Data were
analyzed by stratum to avoid the possibility that the
non-normal distribution of Lp(a) would mask the effects of dietary
fatty acids. In particular, subjects with low levels of Lp(a) would not
be expected to have important changes in response to diet. We also
attempted to stratify our data further to ascertain whether subjects
with the very highest levels according to sextile ranking had increases
in Lp(a) levels that were clearly related to intake of
trans-fatty acids. We performed analyses both within
sextile and using the sextile as a stratifying variable. We report
data for 3 strata (Table 3
) because tests of the fit of the resulting
models showed no evidence that more than 3 strata would describe the
data more accurately.
For each of the 3 strata, the Sat diet produced lower levels of Lp(a) than did the other diets. Subjects who had high levels of Lp(a) at baseline had slightly higher Lp(a) levels when they ate the High Trans (56.0±0.6 mg/dL) than when they consumed the Mod Trans (53.4±0.6 mg/dL) or Oleic (53.2±0.6 mg/dL) diets. These differences were nominally significant (i.e., statistically significant without correction for multiple comparisons, P<.03). However, the effect of the High Trans diet was not statistically significant after Bonferroni correction for multiple comparisons, suggesting that the increase could have been due to chance. Replacing cis- with trans-fatty acids had no effect on Lp(a) levels of subjects who had low or medium levels of Lp(a) at baseline and no effect when all subjects were considered collectively. The Lp(a) levels were not correlated with LDL cholesterol levels (r<.02; P>.4 for all diets).
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Discussion |
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We were particularly interested in the effect of trans-fatty acids on Lp(a) given the recent evidence that the ingestion of partially hydrogenated vegetable oils adversely affects lipoprotein profiles.10 13 14 15 16 17 If trans-fatty acids also increase Lp(a) levels, which may be an independent risk factor for coronary heart disease,1 2 3 4 5 then public health concerns about the widespread use of food products containing these fats might justifiably become stronger.
Trans-fatty acids are produced from cis-isomers
during the hydrogenation of vegetable oils. Partially hydrogenated
vegetable oils are widely used in margarines, shortenings, commercial
frying fats, and baked goods, in large part because they provide the
physical properties and stability of saturated fats but contain less
saturated fatty acids than the traditional hard fats. Food composition
data for trans-fatty acids of individual foods are sparse,
so data concerning the typical intake of trans-fatty acids
in the United States are less precise than for most other types of
fatty acids.31 Estimated intakes of trans-fatty
acids based on availability in the food supply range from 8.1
g32 to 13.3 g33 per person per day, or
approximately 3% to 6% of energy for most adults in the U.S.
population. We chose to add trans-fatty acids from partially
hydrogenated vegetable oils at 3% of energy intake because we estimate
that this level approximates the average level of U.S. consumption.
Recognizing that some individuals consume larger amounts, we also added
trans-fatty acids at a higher level, 6% of energy. The Mod
Trans diet provided 6.7 g of trans-fatty
acids for women at their average intake level of about 8.40 MJ (2000
kcal) and 10.7 g for men at their average intake level of about
13.39 MJ (3200 kcal) from partially hydrogenated vegetable oils. The
High Trans diets provided about twice these levels. These
diets contained additional (
2 g/d) trans-fatty
acids from natural sources (largely dairy products), as did the
Oleic and Sat diets.
Katan and coworkers9 found median levels of Lp(a) to be 73% and 41% higher when 10% of energy as trans-monounsaturated fatty acids replaced an equivalent amount of cholesterol-raising saturated fatty acids (lauric, myristic, and palmitic acids) or oleic acid, respectively. In another experiment from that laboratory, median levels of Lp(a) increased by 23% when 8% of energy from trans-fatty acids replaced either linoleate or stearate.9 Nestel et al.10 reported that trans-fatty acids at 7% of energy produced a 19% increase in Lp(a) levels when elaidic acid was substituted for palmitic acid.
However, Lichtenstein et al.13 observed no increase in
Lp(a) levels when trans-fatty acids were fed at a more
moderate level, 4% of energy, by replacing corn oil with corn oil
margarine. Similarly, after adjusting for multiple comparisons, we
found no significant effects on Lp(a) levels as a result of
substituting either 3% or 6% of energy as trans-fatty
acids at the expense of oleic acid. However, our data suggest that high
levels of trans-fatty acids may be associated with small
increases in Lp(a) levels in a subpopulation, those with high levels of
Lp(a). This conclusion is based on the observation that the 19 subjects
with high baseline levels of Lp(a) (30 mg/dL) had, on average,
a 5% increase in Lp(a) when they consumed the diet with 6% of energy
as trans-fatty acids rather that the diets with oleic acid
or with 3% of energy as trans-fatty acids. This group also
exhibited a 10% increase in Lp(a) levels when 6% of energy as
trans-fatty acids replaced 6% of energy as saturated fatty
acids. The biological significance of these changes is unknown.
The dietary trans-monounsaturates in our study and those from studies by Katan and coworkers9 14 15 were similar in that at least 98% of the total dietary trans-fatty acids were 18:1 monounsaturates. They differed, however, in the distribution of trans-isomers. The predominant trans-isomers in the Mod Trans and High Trans diets were 18:1n-8 (27.5%), 18:1n-7 (21.9%), 18:1n-9 (18.8%), 18:1n-6 (15.0%), and 18:1n-10 (14.2%). The distribution of trans-isomers used by Katan and coworkers9 14 15 was: 18:1n-9 (29.1%), 18:1n-8 (23.2%), and 18:1n-7 (20.6%). The relative distribution of trans-monoenes in our study is typical of fats hydrogenated in the United States. Thus, a possible explanation for the lack of Lp(a) response in our study and that of Lichtenstein et al.13 may be the differing pattern of trans-monoenes produced by the different hydrogenation methods used in the United States and for the Dutch studies. The hydrogenation method used in the United States produces less elaidic acid (18:1n-9), and elaidic acid has been fed at higher levels in studies reporting that trans-fatty acids affect Lp(a) levels.9 14 15
Significant, although weak, correlations between levels of Lp(a) and of apoprotein B or LDL have been noted by some,5 34 35 but not all,14 36 37 investigators. We found no relationships between Lp(a) levels and levels of other lipoproteins; correlations were very small and none was significantly different from zero. Our data are consistent with the concept that Lp(a) is independently regulated. Hepatic production may be the dominant factor influencing levels of Lp(a).38
The diet enriched with saturated fatty acids produced significantly lower levels of Lp(a) than did diets enriched with cis-monounsaturated and trans-monounsaturated fatty acids. This finding is consistent with those of previous reports that the cholesterol-raising saturated fatty acids (lauric, myristic, and palmitic acids) produce lower Lp(a) concentrations than oleic acid9 and that butter produces lower levels of Lp(a) than either partially hydrogenated safflower oil or partially hydrogenated fish oil.11
Assuming that the standard errors observed in this study were the true
underlying standard errors associated with diet, this study had an 80%
power to detect changes (in mg/dL) of 0.6, 2.1, and 4.4 for the
low-, medium-, and high-Lp(a) groups, respectively, and of 1.6 for the
subjects collectively. These values were calculated with a Bonferroni
adjustment for multiple comparisons (
=.05/3). Using a nominal
level of .05, the study had an 80% power to detect changes (in
mg/dL) of 0.5, 1.9, and 3.7 for the low-, medium-, and
high-Lp(a) groups, respectively, and 1.4 for the subjects collectively.
Thus, the study most likely could detect meaningful differences in
Lp(a) levels that occurred in response to diet. We detected some
differences that were smaller, yet statistically significant, than
those for which we had 80% power.
In summary, our data suggest that for individuals with high levels of Lp(a) trans-fatty acids may adversely affect Lp(a) levels. This finding, which was statistically significant only prior to correcting for multiple comparisons, must be considered suggestive rather than conclusive. If, as generally believed, a high level of Lp(a) is an important risk factor for cardiovascular disease, then the biological significance of these changes will best be evaluated by conducting dietary studies of individuals with high levels of Lp(a). Perhaps more pertinent for the general population is the impact of saturated fatty acids on Lp(a) levels. Saturated fatty acids not only appear to lower Lp(a) levels, but also do so consistently, regardless of the initial Lp(a) level. Because of the well-known ability of saturated fatty acids to raise LDL levels, it remains important to clarify the impact of trans-fatty acids on Lp(a) relative to viable dietary alternatives, such as oleic acid.
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Acknowledgments |
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We thank the Institute of Shortening and Edible Oils, Washington, DC, and member companies for their financial support and for supplying test fats and analytical data for these fats. We thank Dr. Edward Emken, National Center for Agricultural Utilization Research, Agricultural Research Service, for analyzing cis- and trans-fatty acid positional isomers in the test fats and experimental diets. We thank Priscilla Steele, RD, and the staff of the Human Studies Facility, Beltsville Human Nutrition Research Center, for preparing the controlled diets. Jennifer Jenner was supported by National Institutes of Health training grant T32AG0029.
Received August 13, 1996; accepted February 19, 1997.
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