Upload
others
View
2
Download
0
Embed Size (px)
Citation preview
Am J Clin Nutr 1995;61:1129-39. Printed in USA. © 1995 American Society for Clinical Nutrition 1129
Plasma cholesterol-predictive equations demonstrate thatstearic acid is neutral and monounsaturated fatty acids arehypocholesterolem ic1 �
Shaomei Yu, Janice Derr, Terry D Etherton, and PM Kris-Etherton
ABSTRACT In the present study we used regression anal-yses to evaluate the effects of stearic acid (18:0) on total
cholesterol (IC), low-density-lipoprotein-cholesterol (LDL-C),
and high-density-lipoprotein-cholesterol (HDL-C) concentra-tions (rnrnol/L). Using data from 18 articles, we developed thefollowing predictive equations (monounsaturated fatty acids,MUFAs; polyunsaturated fatty acids, PUFAs): �TC =
0.0522�12:0-16:0 - 0.0008M8:0 - 0.0124 �MUFA -
0.0248 i�PUFA; t�LDL-C = 0.0378z�12:0-16:0 +
0.0018M8:0 - 0.0178z�MUFA - 0.0248z�PUFA; �HDL-C= 0.0160M2:0-16:0 - 0.0016M8:0 + 0.0101�MUFA +
0.0062L�PUFA. Our analyses revealed that unlike the otherlong-chain saturated fatty acids (SFAs), steanic acid had no
effect on IC and lipoprotein cholesterol concentrations in men
and women. MUFAS elicited an independent hypocholester-
olemic effect that we believe is due to the small amount of
12:0-16:0 in the experimental diets evaluated. The observation
that steanic acid has unique effects on IC, LDL-C, and HDL-C
provides additional compelling evidence that it be distin-
guished from the other major SFAS in blood cholesterol pre-
dictive equations. Am J Clin Nutrl99S;61:1 129-39.
KEY WORDS Saturated fatty acids, polyunsaturated fattyacids, monounsaturated fatty acids, steanic acid, plasma totalcholesterol, high-density-lipoprotein cholesterol, low-density-
lipoprotein cholesterol
Introduction
The quantitative responsiveness of plasma lipids to dietary
fat and cholesterol was first reported by Keys et al (1, 2) andHegsted et al (3) “�‘30 y ago. Both groups developed predictive
equations using regression analysis of data collected from
feeding experiments conducted mostly with middle-aged men.The effects of diet on different lipoprotein classes [eg, low-
density-lipoprotein-cholesterol (LDL-C) and high-density-li-
poprotein-cholesterol (HDL-C) concentrations] were not as-sessed in early studies, nor were sex effects examined.
Recently, Mensink and Katan (4) and Hegsted et al (5) devel-
oped regression equations to predict dietary responsiveness of
total cholesterol, LDL-C, and HDL-C in both men and women.
Because all of the major long-chain saturated fatty acids(SFAs) in the diet were grouped together in the latter studies,
it is not possible to examine the specific effects of stearic acid
on total and lipoprotein cholesterol concentrations. The early
investigations, however, reported that steanic acid (18:0) was
not hypercholesterolemic compared with the other long-chain
SFAs. More recently we suggested (based on a limited data set)that steanic acid has a cholesterolernic effect that is cleanly
different from that of other long-chain SFAs (6). Despite the
consistent findings over the years that steanic acid is a unique
long-chain SFA, it is still frequently grouped with other SFAs
in both individual diet studies, as well as in studies designed to
develop serum cholesterol predictive equations.
Earlier meta-analysis equations suggested that monounsat-urated fatty acids (MUFAs) had no effect on plasma cholesterol
concentrations (1-3). However, clinical studies consistently
showed that diets rich in MUFAs (and low in SFAs) decreased
plasma total cholesterol and LDL-C as much as did diets rich
in polyunsaturated fatty acids (PUFAs) or low-fat, high-canbo-
hydrate diets (7-12). The reason for the discrepancy between
clinical studies and meta-analyses is not clear.
The present study was conducted to more comprehensively
examine the effects of steanic acid, MUFAS, and other fattyacids on total and lipoprotein cholesterol concentrations in both
men and women. We conducted an exhaustive literature searchof controlled feeding studies published between 1970 and 1993in which the effects of dietary fatty acid manipulations on
plasma lipids and lipoproteins were reported. Eighteen studies
were selected that met our inclusion criteria (that data for
dietary steanic acid and other fatty acid classes be reported).
Using these data, we developed new regression equations to
predict the responsiveness of serum lipids and lipoproteins to
individual dietary fatty acids in both men and women.
Methods
Selection of studies
By searching MEDLINE and the references in the papers we
identified, we selected 18 articles published between 1970 and
1 From the Departments of Nutrition, Statistics, and Dairy and Animal
Science, and The Graduate Program in Nutrition, The Pennsylvania State
University, University Park.
2 Supported in part by The Pennsylvania Agricultural Experiment
Station.
3 Address reprint requests to PM Kris-Etherton, Nutrition Department,
The Pennsylvania State University, 5-126 Henderson Building, University
Park, PA 16802.
Received September 12, 1994.
Accepted for publication January 5, 1995.
at PE
NN
SY
LVA
NIA
ST
AT
E U
NIV
PA
TE
RN
O LIB
RA
RY
on February 21, 2013
ajcn.nutrition.orgD
ownloaded from
1130 YU El AL
where IC is total cholesterol.
1993 that reported the quantity of individual SFAs or steanic
acid (18:0) and the sum of launic (12:0), myristic (14:0), and
palmitic (16:0) acids, and MUFAs and PUFAS of the expeni-
mental diets (10-27). Dietary fat accounted for 30-40% ofenergy intake in all studies, which is representative of the fat
intake in the United States. The following exclusion criteriawere used to select data for analysis: 1) liquid-formula diets
used as experimental diets (28), 2) diets that were specificallyenriched in trans isomers of unsaturated fatty acids because
this was not our principle focus, 3) diets that were enriched in
very-long-chain (n- 3) polyunsaturated fatty acids (fish oil),
and 4) subjects with familial hypercholesterolemia because ofevidence demonstrating that they may respond differently to
diet (16).
Table 1 summarizes the 18 studies used in our analysis.
Briefly, subjects in the studies analyzed were between the ages
of 19 and 65 y (men) and 18 and 55 y (women). They were
healthy and normocholesterolemic (most had baseline plasma
cholesterol concentrations < 5.17 mmol/L, or 200 mg/dL).They were fed controlled, whole-food diets during the exper-imental periods. The 18 studies yielded 67 data points.
Statistical methods
To predict changes in serum total cholesterol, LDL-C, and
HDL-C concentrations in response to changes in fatty acid
intake (as a percentage of total daily energy intake), we devel-oped equations using multiple-regression analysis. Each data
point (total of 67) represented the difference in the composition
of two particular diets and the difference in the mean serum
total cholesterol, LDL-C, and HDL-C concentrations in sub-
jects on each test diet. For example, a parallel design with a
common baseline diet followed by two test diets yielded two
data points (eg, the differences between the baseline diet andeach test diet). When the diet comparisons were made in arandom order and crossover design study with three test dietsthe study yielded three, six, or nine data points depending onsubject classes (men, women, and/or total). When a study with
three test diets provided mean serum cholesterol concentrations
for all subjects, or of only one sex, the study yielded three datapoints that represented the difference between any two groups.
If the study provided mean serum cholesterol concentrations
for both sexes, the study yielded six data points that repre-sented three data points for each sex. If the study provided
mean serum cholesterol concentrations for all subjects (ie, bothsexes) the study yielded nine data points. The data points
(dependent variable data) in the studies represented the changein mean plasma total and lipoprotein cholesterol concentrationsbetween adjacent dietary periods. The change in the fatty acid
composition of the experimental diets was used as diet data
points (independent variable data). Our set of predictor van-
ables was the difference between dietary periods in the corn-
position of 12:0-16:0, 18:0, MUFAs, and PUFAS. The pre-dicted change in serum and lipoprotein cholesterol was
estimated by using the following equation:
z�TC(z�LDL-C, z�HDL-C) = az�12:0-16:0 + bM8:0
+ c�MUFA + dL�PUFA
The coefficients (a, b, c, and 6) were estimated by least-
squares regression. Analysis of residuals was performed to
check the appropriateness of the regression model used.
Three studies (10, 11, 27) provided the quantities of total
SFAS and the sum of 12:0-16:0. Steanic acid was calculated bysubtracting 12:0-16:0 from total SFAs. If studies provided thequantity of individual fatty acids as gram weight units, we
converted the values to percent of energy. We did not includechange in cholesterol intake in our equations because dailycholesterol intakes in each study were similar among treatmentgroups. Some studies did not report LDL-C concentrations (11,
27). In these studies, we estimated LDL-C from the concen-
tration of total cholesterol, HDL-C, and triglyceride by using
the equation of Fniedewald et al (29). All statistical analyses
were carried out by using the SAS software program (30).
Results
Total cholesterol, LDL-C, and HDL-C in all subjects
Table 1 shows the summary of 18 studies (10-27) used in the
present investigation. Seventeen of the studies reported total
cholesterol and yielded 55 data points. Sixteen studies reported
HDL-C and yielded 49 data points. For 17 studies, LDL-Cvalues were reported or could be calculated, which yielded 61
data points. The regression equations developed for predicting
the relationship between total cholesterol, LDL-C, HDL-C, and
fatty acid intake are as follows:
�TC (mmolIL) = 0.0522*M2:0_16:0 - 0.0008M 8:0
- 0.0124**�MUFA - 0.0248*z�PUFA (R2 = 0.90) (1)
[SIC (rng/dL) = 2.02*z�12:0_16:0 � 0.03M8:0
- 0.48**z�MUFA _0.96*���PUFA]
�LDL-C (mmol/L) = 0.0378*M2:0_16:0 + 0.0018z�18:0
- 0.0178*z�MUFA _ 0.0248*z�PUFA (R2 = 0.90) (2)
[L�LDL-C (mg/dL) = 1.46*M2:0_16:0 + 0.0Th18:0
- 0.69*z�MUFA _0.96*z�PUFA]
AHDL-C (mmol/L) = 0.0160*z�12:0_16:0 - 0.0016M8:0
+ 0.0101*z�MUFA + 0.0062*�PUFA(R2 = 0.59) (3)
[L�HDL-C (mg/dL) = 0.62*M2:0_16:0 � 0.06�18:0
+ 0.39*z�MUFA + 0.24*L�PUFA]
*,* *Regression coefficients are significantly different from 0:
*P < 0.05, **� < �
The equations predict the mean change (�) in a particular
lipid or lipoprotein (mmol/L) in response to changes in daily
dietary energy intake of fatty acids. For example, when other
fatty acids remain constant, for every 1 % increase in energy
from 12:0-16:0 fatty acids, total cholesterol is expected toincrease 0.0522 mmol/L, whereas a 1% increase in PUFA
lowers total cholesterol by 0.0248 mmol/L.
at PE
NN
SY
LVA
NIA
ST
AT
E U
NIV
PA
TE
RN
O LIB
RA
RY
on February 21, 2013
ajcn.nutrition.orgD
ownloaded from
TABLE 1
Summary of well-controlled studies used in the present investigation’
Reference Men Women Age
Study
design TC Test diets
Dietary composition
12:0-16:0 12:0 14:0 16:0 18:0 MUFA PUFA Other
n n y mmol/L % of energy
6 6 21-56 x
8 - 19-32 x
15 34 19-52 x
36 - 22-32 �
4 1 28-67
26 - 27-57
26 30 18-49
21 - 20-65
Premenopausal
0.0
0.4
2.6
1.5
1.5
x 4.68 Palm oil
Olive oil
Sunflower oil
12.3 3.1 13.5
6.3 2.5 21.4
5.8 2.6 12.4
Young � 4.99 Control
Olive oil
Sunflower oil
Young x 4.76 SFA
Oleate
26 30 Young x 5.04 Stearate
Linoleate
17 24 ./ 4.76 American diet
15 24 Step 1 diet
16 26 FA
20 13 22-41 x <5.69 Coconut oil
Palm oil
Olive oil
27 - 30-63 x 4.55-7.32 Habitual
Oleic acid
Palmitic acid
33 26 x 3.10-5.30 Olive oil
Cocoa butter
Soybean oil
Butter
30 27 x Milk chocolate
Cocoa butter
Mix
Butter
18 21-43 x 5.12 Step 1 diet
Walnuts
30 40-65 x
- 0.01 0.1
- 0.01 0.2
- 0.01 0.1
- 0.8 3.5
- 0.4 0.7
- 0.02 0.2
- 0.2 0.7
- 0.8 3.3
- 0.3 0.8
- 0.1 0.2
4.5 1.4 27.2
9.3 11.4 13.2
4.5 1.7 10.1
9.3 4.5 10.1
9.2 10.3 12.1
9.4 11.4 13.3
9.2 10.3 12.3
9.5 4.7 10.4
5.5 2.2 8.8
3.8 1.6 7.4
8.8
9.2
4.8
14.7
x, a crossover study design; TC, total cholesterol; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid;
CHOLESTEROLEMIC EFFECFS OF 18:0 AND MUFA 1131
Harris et al (13; 1983)
McDonald et al (14; 1989)
Mensink and Katan (15;
1990)
Ginsberg et al (12; 1990)
Friday et al ( 16; 1991)
Nestel et al (17; 1992)
Zock and Katan (18; 1992)
Mata et al (19; 1992)
Mensink et al (20; 1992)
Experiment 1
Experiment 2
Experiment 3
Barr et al (21; 1992)
Ng et al (22; 1992)
Nestel Ct al (23; 1992)
Kris-Etherton (24; 1993)
Study 1
Study 2
Sabate et al (25; 1993)
Grande et al (26; 1970)
I ,, parallel study design;
SFA, saturated fatty acid.
27 31
14 15
13 16
25 34
4.97 Control
Vegetable oil
4.42 Mixed fat
Canola oil
Sunflower oil
4.76 Oleic acid
SFA
- American diet
Step I diet
MUFA diet
4.84 Butter
Safflower oil
4.99-7.50 Control 1
Control 2
Blend 1
Blend 2
4.84 Linoleate
Stearate
Cocoa butter
Mixture
Palm oil
Mixture
- - - 7.9 7.1 17.1
- - - 5.0 1.3 11.3
- - 1.3 8.2 4.2 15.0
- - 0.4 3.1 1.1 20.0
- - 0.4 3.9 2.2 7.0
- 0.5 0.5 4.7 3.0 24.1
- 3.4 2.7 8.1 3.5 14.7
- 3.9 2.6 6.9 3.1 11.7
- 0.7 0.9 4.9 2.4 11.0
- 0.8 0.9 5.2 2.3 17.9
- - 3.2 9.3 4.7 10.2
- - 0.1 2.6 1.0 4.5
- 0.1 0.3 14.4 2.8 15.0
- 0.1 0.3 13.8 2.6 15.0
- 0.1 0.2 7.9 4.3 16.0
- 0.0 0.1 6.5 4.9 16.0
- 0.7 0.9 5.8 2.8 15.8
- 0.5 1.0 5.7 11.8 16.6
- 1.2 3.2 9.3 4.1 11.5
- 0.7 1.4 6.8 3.2 15.1
- 0.9 1.3 6.2 3.4 10.8
- 3.4 2.7 8.1 3.5 14.7
- 0.5 0.5 4.7 3.0 24.1
- 0.5 1.0 5.7 11.8 16.6
- 0.7 0.9 5.8 2.8 15.8
- 1.3 1.8 7.4 3.2 14.5
- 0.5 0.9 5.1 2.2 13.2
- 1.0 1.6 6.1 2.8 10.8
- 12.5 5.4 4.9 1.4 3.9
- 0.3 0.5 13.4 1.8 14.0
- 0.1 0.2 6.3 1.9 21.8
- 0.6 2.3 8.4 3.8 11.9
- 0.2 0.6 5.2 2.3 19.0
- 0.3 0.9 9.8 2.3 14.0
- - - 10.1 11.5
- - - 9.9 11.4
- - - 12.8 12.5
- - - 2.4 12.1
7.9
22.9
7.0
10.0
22.0
4.6
3.4
9.7
10.4
10.5
1.6
25.0
6.0
6.0
10.0
11.0
12.5
4.3
3.2
3.3
12.5
4.6
7.9
12.7
3.4
4.6
4.3
12.5
8.0
7.8
6.5
0.9
3.7
2.9
4.0
7.0
8.0
2.3
2.1
17.8
1.7
1.8
2.1
1.7
1.6
9.5
16.5
2.7
2.8
3.6
3.8
at PE
NN
SY
LVA
NIA
ST
AT
E U
NIV
PA
TE
RN
O LIB
RA
RY
on February 21, 2013
ajcn.nutrition.orgD
ownloaded from
Observed Change In TC (mmoIIL)
1132 YU El AL
TABLE 1 continued
Reference Men Women Age
Study
design TC Test diets
Dietary composition
12:0-16:0 12:0 14:0 16:0 18:0 MUFA PUFA Other
F, n y mmoLfL % of energy
Brussaard et al (27; 1982) 23 12 19-30 / 4.63 Low-fat diet
Medium fat diet
10.0
6.0
-
-
- - 5.0 12.0
- - 2.0 11.0
5.0
11.0
-
-
Mensink and Katan
(11; 1987) 24 24 18-59 / 5.07 Control
Low-fat diet
Olive oil
13.9
4.1
6.8
-
-
-
- - 6.1 12.4
- - 2.6 9.3
- - 3.0 24.0
4.1
5.2
5.1
-
-
-
Mensink and Katan
(10; 1989) 27 31 20-48 / 4.81 Control
Olive oil
Sunflower oil
13.7
8.9
8.4
-
-
-
- - 5.6 11.6
- - 4.0 15.1
- - 4.2 10.8
4.6
7.9
12.7
-
-
-
Based on our equations, SFAS (12:0, 14:0, and 16:0) signif-icantly increased total cholesterol, LDL-C, and HDL-C con-
centrations. Both MUFAs and PUFAS significantly decreased
total cholesterol and LDL-C, whereas both significantly in-
creased HDL-C. 18:0 had no significant effect on any lipid or
lipoprotein concentration.
Figures 1, 2, and 3 show the association between the ob-
served and the predicted changes in total cholesterol, LDL-C,
and HDL-C for equations 1 (data points, n = 55), 2 (n = 61),
and 3 (n = 49), respectively. There was a strong correlation
between the observed and predicted change in plasma total
cholesterol (r = 0.81), LDL-C (r = 0.78) and HDL-C (r =
0.69) when using the equations we generated.
-I
0EE
C.)I-
C
01C
C.)
�0SU
�0S
0.
FIGURE 1. Correlation between the observed and predicted change in
serum total cholesterol (TC) (n = 55 observations). Each point refers to a
specific test diet for one of the studies in Table 1. Predicted values were
calculated for each particular diet from equation 1: L�TC = 0.0522M2:O-
16:0 - 0.0008M8:0 - 0.0124�MUFA - 0.0248�PUFA, where LVFC is
the predicted change in serum TC concentration (mmol/L) as a function of
changes in the percent of energy from dietary fatty acids. The Pearson
correlation coefficient between observed and predicted values (r) is 0.81
(the coefficient of multiple correlation for the equation R = 0.95).
In 14 studies (12-25) the major individual fatty acids in the
experimental diets were reported. These studies yielded 47 data
points that were used to calculate the cholesterolernic effect of
individual fatty acids. One study did not report the total cho-lesterol concentration and two studies did not report theHDL-C concentration. The predictive equations derived for
both sexes are as follows:
A�TC (mmol/L) = 0.0248M2:0 + 0.1443*�14:0
+ 0.0277**M6:0 + 0.01442M8:0 - 0.0044�MUFA
- 0.0171 **�PUFA(R2 = 0.95) (4)
[z�IC (mg/dL) = 0.96�12:0 + 5.58*iM4:0 + 1.07**M6:0
+ 0.55M8:0 - 0.1ThMUFA - 0.66**z�PUFA]
�HDL-C (mmol/L) = 0.0186**z�12:0 + 0.0036z�14:0
+ 0.0072**L\16:0 _0.0039M8:0 + 0.0075**L\MUFA
+ 0.0028**zWUFA(R2 = 0.68) (5)
[z�HDL-C (mg/dL) = 0.72**z�12:0 + 0.14M4:0
+ 0.28**M6:0 _ 0.15�18:0 + 0.29**�MUFA
+ 0.11z�PUFA]
*,* *Regression coefficients are significantly different from 0:
*P < 0.05, **� < �
For the change in total cholesterol, the regression coeffi-
cients of M4:0, M6:0, and L�PUFA were significantly differ-
ent from zero; for �HDL-C, the regression coefficients of
M2:0, M6:0, and �MUFA were significantly different from
zero. The predictive equation for LDL-C was similar to that for
total cholesterol (equation not shown).
Effects offatty acids on total cholesterol, LDL-C, and HDL-
C in men and women
Table 2 presents the linear-regression equations for men andwomen that predict changes in total cholesterol, LDL-C, and
HDL-C in response to changes in fatty acid intake.
at PE
NN
SY
LVA
NIA
ST
AT
E U
NIV
PA
TE
RN
O LIB
RA
RY
on February 21, 2013
ajcn.nutrition.orgD
ownloaded from
-0.2 0.0 0.2 0.4 0.6 0.8 1.0
Observed Change In LDL-C (mmol/L)
Observed Change In HDL-C (mmolIL)
CHOLESTEROLEMIC EFFED’S OF 18:0 AND MUFA 1133
TABLE 2
Estimated regression coefficients of equations for predicting mean
changes (�) in total cholesterol (TC), LDL, and HDL cholesterol for
men and women
Cholesterol
and sex
CoefficientsData
points
Number
of
studiesM2:0-16:0 M8:0 �MUFA �PUFA
n nL�TC
Men 0.0489’ -0.0018 -0.0137 -0.0274’ 35 13
Women 0.04812 -0.0109 -0.0197 -0.0253 1 1 6
L�LDL
Men 0.0318’ 0.0034 -0.0181’ -0.030’ 33 13
Women 0.03572 -0.0023 -0.0253 -0.0220 15 7
�HDL
Men 0.0142’ -0.0010 0.0091 ‘ 0.0()722 29 12
Women 0.0142’ -0.0083� 0.0080 -0.0021’ 1 1 6
1.2 Significantly different from zero: ‘ P < 0.01, 2 p < 0.05.
3 Significantly different from men for HDL cholesterol, P < 0.01.
FIGURE 2. Correlation between the observed and predicted change in
serum LDL-cholesterol response (n = 61 observations). The predicted
responses were calculated by using equation 2: �LDL-C = 0.0378M2:0-
16:0 + 0.0018�18:0 - 0.0178 L�MUFA - 0.0248�PUFA. The Pearson
correlation coefficient between observed and predicted values (r) is 0.78
(the coefficient of multiple correlation for the equation R = 0.94).
Total cholesterol. Based on the regression equations developed,
12:0-16:0 significantly increased total cholesterol in both men and
women. The regression coefficients of 18:0 for L�TC were not
�1
0EE
0
�1
I
C
001CS
.C0
�00U
�00
0.
FIGURE 3. Correlation between the observed and predicted change in
serum HDL-cholesterol concentrations (n = 49 observations). The pre-
dicted values were calculated by using equation 3: �HDL-C = 0.0160M2:
0-16:0 - 0.0016M8:0 + 0.0101 L�MUFA + 0.0062L�PUFA. The Pearson
correlation coefficient between observed and predicted values (r) is 0.69
(the coefficient of multiple correlation for the equation R = 0.77).
significantly different from zero in both sexes, thus, 18:0 had a
neutral effect on total cholesterol. PUFA decreased total choles-
terol in both men and women, but the regression coefficient wassignificantly different from zero only in men. There was no sig-
nificant sex difference. MUFA decreased total cholesterol in both
men and women; however, the decrease was not statistically sig-
nificant.
LDL-C. The changes in LDL-C were similar to the changes in
total cholesterol. 12:0-16:0 significantly increased LDL-C concen-
trations in both men and women. 18:0 elicited a neutral effect in
both sexes. Both MUFAs and PUFAs decreased LDL-C in both
men and women; however, the decrease was significant only in
men. The LDL-C response to all fatty acid classes between men
and women, however, was not significantly different.
HDL-C. 12:0-16:0 significantly increased HDL-C concentra-
tions in both men and women. MUFA increased HDL-C concen-
trations in both sexes, but the increase was only significant for
men. When 18:0 and PUFAs were dropped from the equation for
women (the regression coefficients for both of them were not
significantly different from zero), the equation for predicting the
changes in HDL-C was as follows:
�HDL-C (mmollL) = 0.0142*M2:0_16:0 + 0.0083**z�MUFA
[L�HDL-C (mg/dL) = 0.55*�12:0_16:0 + 0.32**z�MUFA]
(6)
In this equation, the regression coefficient for MUFAs for
HDL-C was significantly different from zero. PUFAs increased
HDL-C concentrations in men compared with women. The sex
difference was significant (P < 0.001).
Figures 4, 5, and 6 show the mean changes in total choles-
terol, LDL-C, and HDL-C in response to changes in fatty acid
intake (expressed as a percentage of daily dietary energy in-
take) for men and women. In Figure 4, a 1% increase in PUFA
(with other fatty acids remaining constant) lowered total cho-
lestenol by 0.0274 mmol/L in men and 0.0253 mmolfL in
women; in Figure 6, a 1% increase in PUFA raised HDL-C by
0.0072 rnrnol/L, whereas it lowered HDL-C by 0.0021 mmol/L
in women. This sex effect was significant for HDL-C in ne-sponse to PUFA (P < 0.01).
at PE
NN
SY
LVA
NIA
ST
AT
E U
NIV
PA
TE
RN
O LIB
RA
RY
on February 21, 2013
ajcn.nutrition.orgD
ownloaded from
S
C0U
0C0SSS
01S
0
I-.
�1
S
CSU
S00
C0
SS001
0
0
-JCI
A C12-C16 is cii �s MUFA
Fatty AcidsFatty Acids
Discussion
The present study provides additional evidence to support
the position that steanic acid is a unique long-chain SFA. The
primary objective of our study was to evaluate the effects of
S
CSU
S00
C0SSS
01S
0-JC-J.�
Fatty Acids
1134 YU El AL
FIGURE 4. Comparison of the predicted change in total cholesterol
(TC) response to the change in the percent of energy from fatty acids for
men and women, the equations used were as follows: for men, �TC
0.0489M2:0-16:0 - 0.0018M8:0 - 0.O13ThMUFA - 0.0274�PUFA;
for women, L�TC = 0.0481�12:0-16:0 - 0.0109M8:0 - 0.O19ThMUFA
- 0.O253L�PUFA. No sex effects were observed.
FIGURE 5. Comparison of the predicted change in LDL-C with the
change in the percent of energy from fatty acids for men and women. The
equations used were as follows: for men, �LDL-C = 0.0318M2:O-16:0 +
0.0034M8:0 - 0.0181i�MUFA - 0.030 �XPUFA; for women, i�LDL-C
0.0357M2:0-16:0 - 0.0023M8:0 - 0.0253�MUFA - 0.0220L�PUFA.
Sex effects were not significant.
FIGURE 6. Comparison ofthe predicted change in HDL-C in men with
that in women. The equations used were as follows: for men, �HDL-C =
0.0142M2:0-16:0 - 0.O010�18:O + 0.0O9l�MUFA + 0.0072�PUFA;
for women, L�HDL = 0.0142 �12:0-16:0 - 0.0O83�18:O +
0.0080�MUFA - 0.O021�PUFA. Sex differences were significant for the
responsiveness of serum HDL-C to the change in dietary 18:0 and PUFAs
(* p < o.oi women compared with men).
stearic acid on total and lipoprotein cholesterol concentrations
in women and men. A distinguishing feature of our approach
was that we included only those studies for which we were able
to determine the intake of the principle fatty acid of interest, ie,
steanic acid. As expected, we found that the other long-chain
SFAS (ie, 12:0-16:0) are hypercholesterolemic. Thus, because
stearic acid is cleanly different, we propose that it be distin-
guished from the other long-chain SFAs and not be grouped
with them when estimating the plasma cholesterol response to
changes in dietary SFAs. Whereas Keys et al (1) excluded
steanic acid from their predictive equations, the fact that we
only found 18 studies that separated steanic acid from the other
long-chain SFAS indicates that, for the most part, many scien-
tists have not recognized the importance of considering steanic
acid separately. In addition, although steanic acid had a neutral
effect on total cholesterol and LDL-C and HDL-C in men, our
study suggests that it may lower HDL-C in women. This
observation is significant because it is based on data from 13
studies.
Another point of interest is that MUFAs may have a greater
cholesterol-lowering effect in both men and women than pre-
viously thought. This is based on our observation that the
regression coefficients for total cholesterol and LDL-C were
significantly negative (equations 1 and 2); the magnitude of the
response was half that reported for PUFAs. Furthermore, the
sex effect of PUFAs on HDL-C provides further support for the
hypothesis that there are significant differences between sexes
with respect to the cholesterolemic effects of individual fatty
acids. It will be important to verify these observations withwell-controlled feeding studies.
at PE
NN
SY
LVA
NIA
ST
AT
E U
NIV
PA
TE
RN
O LIB
RA
RY
on February 21, 2013
ajcn.nutrition.orgD
ownloaded from
CHOLESTEROLEMIC EFFECTS OF 18:0 AND MUFA 1135
Stearic acid
The early evidence (1-3) suggesting that steanic acid does
not raise plasma total cholesterol concentrations was confirmed
in the present study. The regression coefficients for steanic acid
in the present study are not significantly different from zero (P
= 0.3-0.9). When steanic acid is deleted from equations 1, 2,
and 3, the regression coefficients for the nest of the fatty acid
classes do not change as shown below:
�TC (mmolIL) = 0.0522*z�12:0_16:0 - 0.0122**�MUFA
(R2 0.90)
- 0.0243*z�PUFA (7)
[�TC (mg/dL) = 2.03*z�12:0_16:0 � 0.47**�MUFA
�LDL-C (mmol/L) = 0.0372*�12:0_16:0
(R2 0.89)
- 0.94*z�PUFA]
- 0.0184*�MUFA _ 0.0256*z�PUFA (8)
[L�LDL-C (mg/dL) = 1.44*�12:0_16:0 � 0.71*�MUFA
�HDL-C (mmol/L) = 0.0163*M2:0_16:0
(R2 0.59)
- 0.99*zWUFA
+ 0.0101*L�MUFA + 0.0062*�PUFA (9)
[L�HDL-C (mg/dL) 0.63*�12:0_16:0 + 0.39*z�MUFA
+ 0.24*�PUFA]
Our results also agree with the predictive equations of Den
et al (6) that showed that steanic acid is not a hypercholester-
olemic SFA. Interestingly, the latter study reported a signifi-
cantly negative regression coefficient for steanic acid (-0.0181
for mmolfL, or -0.7 for mg/dL) for total cholesterol, which was
similar to that reported by Hegsted et al (3) in 1965 (ie,
-0.0129 for mrnol/L, or -0.5 for rng/dL) yet less than that
reported for PUFAs. It is clear that steanic acid does not
increase plasma total cholesterol and LDL-C concentrations
compared with other SFAs. However, it is not entirely clean
whether steanic acid truly has a neutral effect or whether, in
fact, it may lower cholesterol concentrations, but less so than
do unsaturated fatty acids. It is possible that the significant
cholesterol-lowering effect of steanic acid in the equations of
Denr et al (6) is due to its high quantity in the test diets.
Well-controlled feeding studies and mechanistic investigations
are needed to resolve the actual cholestenolemic effect of
steanic acid. Irrespective of whether steanic acid is neutral or
lowers cholesterol concentrations, sufficient evidence has ac-
cumulated (including that reported herein) to recommend that
it be distinguished from the other long-chain SFAs in blood
cholesterol predictive equations.
Early studies suggested that steanic acid might have a neutral
effect or slightly lower HDL-C. The present study shows that
the effect of steanic acid on HDL-C is affected by sex. The
regression coefficient (which is negative) for 18:0 for HDL-C
is larger for women than for men. Steanic acid appears to have
a neutral effect on HDL-C in men, whereas it appears to lower
HDL-C in women. A lowering effect of steanic acid on HDL-C
was also supported by Denke and Grundy (31) and Bonanome
and Grundy (32), who reported that a liquid-formula diet high
in steanic acid tended to lower HDL-C by 0.06 mmol/L (2.3
mg/dL) compared with a formula diet high in palmitic acid and
by 0.1 mrnol/L (3.9 mg/dL) compared with a formula diet high
in oleic acid (NS). Likewise, Becker et al (33) reported that a
steanate-nich saturated fat diet increased total cholesterol and
LDL-C, whereas it decreased HDL-C when compared withdiets high in MUFAs and PUFAs. In addition, Zock and Katan
(18) found that a stearate-nich diet lowered HDL-C relative to
a linoleate-nich diet (by 0.06 mmol/L, or 2.3 mg/dL, P <
0.001). These results agree with the regression equation re-
ported herein and suggest that relative to other SFAs, and
MUFA and PUFA, steanic acid may lower HDL-C.
Monounsaturated fatty acids
The present study shows that MUFAs significantly decrease
serum total cholesterol and LDL-C and increase HDL-C con-
centrations. As noted, MUFAs were not included in Keys et
al’s equation because they were thought to be a neutral fatty
acid class. We found that MUFAs decreased total cholesterol
and LDL-C, in part, because most of the test diets in the present
study were high in MUFAs. In the studies of Keys et al (2) and
Hegsted et al (3), about one-half of the groups consumed
< 10% of energy as MUFAs (Figure 7). In addition, the test
diets in the present study were significantly higher in steanic
acid and lower in 12:0-16:0 (P < 0.05) (� ± SD: 4.35 ±
3.15% and 9.17 ± 3.83% of energy, respectively) when com-
pared with those reported by Hegsted et al (3) (3.23 ± 2.32%
and 12.38 ± 8.52% of energy, respectively), although the total
quantity of SFAs in both studies was similar (Figure 8).
Based on our results we speculate that the effect of MUFAs
on serum total cholesterol and LDL-C is dependent on the
amount of SFA (and specifically the amount of hypencholes-
terolemic SFA) in the diet. Based on this line of reasoning,
when 12:0-16:0 SFAs in the diet are low, the independent
cholesterol-lowering effect of MUFAs is observed. In contrast,
when 12:0-16:0 SFAs are high, the cholesterol-lowering effect
of MUFAs is obscured, and MUFAs appear to have a neutral
cholesterolernic effect. It must be appreciated that the amount
of SFA in the diet should be viewed in the context of individual
fatty acids. Thus, we believe that it is the amount of 12:0-16:0
SFA in the diet that plays a key role in detenmining thecholesterolernic effect observed for MUFAs. Accordingly, al-
though the amount of steanic acid affects the total amount of
SFA in the diet, because it is not hypencholesterolemic, it doesnot obscure the hypocholesterolemic response to MUFAs.
Thus, we believe that two important conclusions can be drawn
from these findings. First, MUFAs are hypocholesterolernic
(but less so than are PUFAs), as also described by Mensink and
Katan (see below; 4). Second, our results provide further evi-dence to support the argument that steanic acid should not be
grouped with other long-chain SFAs. In agreement with our
findings, animal studies have shown that oleic acid decreases
plasma cholesterol concentrations by increasing hepatic LDL
receptor activity and that stearic acid is neutral (34, 35).
The neutral response to MUFAs reported by the early inves-
tigatons also could be due to the amount of cholesterol in the
at PE
NN
SY
LVA
NIA
ST
AT
E U
NIV
PA
TE
RN
O LIB
RA
RY
on February 21, 2013
ajcn.nutrition.orgD
ownloaded from
3O� b.K.ysetai (2)UiC
a
C,
I
20
10#{149}
. i�rn . .
4 6 8 10 12 14 16 18 20 22 24 26 28
Percentage of Energy as MUFA in Test Diets
0
I-
iiC
IL
Fatty Acids
1136 YU El AL
FIGURE 7. Relative frequency histograms for the distribution of per-
centage of energy as MUFAS in diets in three studies (counting percentage
of test groups).
FIGURE 8. Comparison of the mean percentage of energy from fatty
acids in the test diets of the present study with that in the test diets of the
study of Hegsted et al (3). In the present study, the test diets are higher in
18:0 and lower in 12:0-16:0 when compared with the study of Hegsted et
al (*P < 0.05).
experimental diets. Hegsted et al (3) reported that olive oil,
coconut oil, and safflower oil were cholesterol-raising when
dietary cholesterol intake was > 300 mg/d. In fact, there was a
linear relationship between serum cholesterol and the dietary
cholesterol concentration with these three fats. In the studies of
both Keys et al (2) and Hegsted et al (3), one-half of the
treatment groups consumed > 400 mg cholesterol/d; the aver-
age cholesterol intake was 520 mg/d (range 280-1 1 10 mg/d)
and 390 mg/d (range 116-686 mg/d), respectively. Thus, di-etary cholesterol was a significant variable in their equations.
The change in cholesterol intake was not included in our
predictive equations because daily cholesterol intake was sim-
ilar among treatment groups in each study. The mean choles-
terol intake in the present study (300 mg/d) was lower than that
in the studies of Keys et al (2) and Hegsted et al (3).In support of our findings, Mensink and Katan (4) also
reported that MUFAs lower total cholesterol as noted by the
following equation: L�TC (mmol/L) = 0.056�S’ - 0.003i�M
- 0.0151�P), where 5’ is the sum of launic plus mynistic plus
palmitic acids, M is monounsaturated fatty acids, and P is
polyunsaturated fatty acids. The observation that inclusion of
MUFAs improves equations for predicting serum cholesterolchanges is supported by the study of Berry et al (7). These
investigations found a discrepancy between the observed
changes and predicted changes in cholesterol concentration
when the Keys et al equation is used after changing the amount
of dietary MUFAs. MUFAs significantly decreased total cho-
lesterol and LDL-C concentrations, although not as much as
PUFAS did. Other studies have reported that MUFAs are aseffective as PUFAs in decreasing the plasma cholesterol con-
centration (36-38).
The present study suggests that MUFAs not only decrease
total cholesterol and LDL-C, but also increase HDL-C in both
men and women. Compared with PUFA-rich or low-fat diets,
MUFA-rich diets have been shown to increase HDL-C (9, 11,
19). Other studies, however, suggest that MUFAs do notchange HDL-C concentrations (7, 12). Thus, with respect to
HDL-C, MUFAs appear to be either neutral or have a slight
raising effect.
Otherfatty acids
Lauric, myristic, and palmitic acids. The present study suggests
that collectively, launic, myristic, and palmitic acids significantly
increase total cholesterol, LDL-C, and HDL-C concentrations.
Furthermore, these SFAS increase total cholesterol twice as much
as PUFAS decrease it, which agrees with the early equations of
Keys et al (1, 2) and Hegsted et al (3) as well as those published
more recently by Mensink and Katan (4) and Hegsted et al (5).
It is important to point out, however, that SFAs are not equally
hypercholesterolemic. For example, previous studies have shown
that medium-chain SFAS of carbon length 8-10 and stearic acid do
not raise plasma cholesterol concentrations (1-3, 32, 39), whereas
lauric, mynistic, and palmitic acids are hypercholesterolemic (39,
40). Results of the present study suggest that myristic acid is five
to six times more hypercholesterolemic than either launic acid or
palmitic acid (Eq 4), which agrees with the studies of Hegsted et
al (3) and Mensink and Katan (4), and that 12:0 may be less
hypercholesterolemic than palmitic acid (26).
Some investigators suggested that the effects of palmitic acid on
serum cholesterol may vary depending on the experimental design
used (22, 41). In hypercholesterolemic subjects (> 5.82 mmol/L)
and especially those consuming diets providing > 400 mg choles-
terol/d, dietary 16:0 may expand the plasma pool, but not innormocholesterolemic subjects consuming diets containing < 300
at PE
NN
SY
LVA
NIA
ST
AT
E U
NIV
PA
TE
RN
O LIB
RA
RY
on February 21, 2013
ajcn.nutrition.orgD
ownloaded from
CHOLESTEROLEMIC EFFECTS OF 18:0 AND MUFA 1137
mg cholesterol/d (41). However, in the recent study of Zock et al
(42), the cholesterol-raising effect of palmitic acid in the subjects
consuming 350 mg cholesterol/d in the lowest tertile of initial
cholesterol concentration (3.78 mmol/L) was similar to that of
subjects in the highest tertile (5.97 mmol/L). In the present study,
subjects in most studies consumed 300-400 mg cholesterol/d, and
the results show that 16:0 increases total cholesterol, LDL-C, and
HDL-C concentrations. Although the data that suggest that
palmitic acid is not a potent hypercholesterolemic SFA are scant,
this issue nonetheless should be addressed experimentally within
the context of all other major fatty acids in the diet. Additional,
well-controlled clinical studies need to be conducted to evaluate
the cholesterolemic effects of individual fatty acids.
Mensink and Katan (4) and Hegsted et al (5) reported that SFAS
increase HDL-C concentrations which has been confirmed in the
present study. However, the effects of individual SFAs on the
distribution of cholesterol among the various lipoproteins, espe-
cially on HDL-C, are largely unknown. The present study shows
that 12:0 and 16:0 increased HDL-C; 14:0 had no effect. These
findings were supported by other clinical studies (22, 24, 40). Zock
et al (42), however, recently reported that feeding large concen-
trations of myristic acid (53% of total fat) increased HDL-C by 9%when compared with palmitic acid and oleic acid. In this study,
myristic acid concentrations were considerably higher than those
typically provided in experimental diets because synthetic fats
were fed. Thus, because of limited evidence the specific effects of
individual SFAs on HDL-C remain to be established.
Polyunsaturated fatty acids. In the present study we found a
significant negative correlation between PUFAs and total choles-
terol that is similar to that reported by Keys et al (1) and Hegsted
et al (3). The slightly lower regression coefficient reported herein
for PUFAs is explained by two factors: 1) the inclusion of studies
that provided diets higher in MUFAs than those used by the early
investigators, and 2) the inclusion of MUFAs in the regression
equations (which clearly was indicated because of its significant
cholesterolemic effect).
As noted by Mensink and Katan (4), the specific effects of
PUFAs on total and lipoprotein cholesterol concentrations actually
may be slightly less than was previously thought. Taken together
with the data reported for stearic acid, it is clear that the predictive
equations developed are not only dependent on the experimental
diets fed (and the quantities of specific fatty acids fed), but also on
the inclusion of specific fatty acids in the predictive equations.
Despite this, it is still clear that PUFAs lower total cholesterol and
LDL-C concentrations.
In the equations we developed, there was a positive correlation
between PUFAs and the HDL-C concentration for all subjects
(men and women) and men (the equation for women suggested a
neutral effect of PUFAs on HDL-C). This result agrees with the
equations reported by Hegsted et al (5) and Mensink and Katan (4).
Although the regression coefficients for PUFAs are statistically
significant and positive, they are lower than the regression coef-
ficient for 12:0-16:0, indicating a less potent effect. Some studies
reported (36, 43-45) that PUFAs decreased HDL-C concentra-
tions, however, in those studies, the intake of polyunsaturated fat
was very high, and the ratio of polyunsaturated to saturated fatty
acids (P:S) ranged from 2.0 to 6.5. Erickson et al (46) indicated
that with a cholesterol-free formula diet the plasma cholesterol
concentration is unaffected by changes in the P:S of the diet from
0.1 to 1.6. Another study showed that there is no change in the
HDL-C concentration when subjects are shifted from a diet with a
P:S of 0.7 to a diet with a P:S of 1.3 (47). In most of the studies
reviewed herein, the P:S was < 2.0. The present study suggests
that PUFAs do not decrease HDL-C (and may increase it) despite
significantly decreasing total cholesterol and LDL-C.
Sex effects
The results of the present study suggest that the total and
LDL-C response to diet for women and men is quite similar;
however, there appears to be a difference in the HDL choles-
tenol response to diet between women and men. Specifically,
the relationship between z�PUFAs in the diet and �HDL-C is
significantly positive in men, but not in women. These findings
suggest that PUFAs may increase HDL-C concentrations in
men, but not in women. Moreover, 18:0 has an apparent
HDL-C-lowening effect in women when compared with men.
Because of the limited data available, the findings of the effects
of sex on plasma cholesterol and lipoproteins should be inter-
preted cautiously.
Recently, the question about diet responsiveness in men
compared with women was addressed by several different
investigators. Clifton and Nestel (48) suggested that men and
women differ significantly in their response to dietary fat and
cholesterol; women experienced a greater increase in HDL�,
whereas men had a greater LDL response to changes in diet.
Similar results were reported in a 3-wk residential, lifestyle-
modification study, in which male subjects had a greater de-
crease in total cholesterol (24.4% vs 20.8%) and LDL-C (25%
vs 19.4%) concentrations compared with female subjects,
whereas female subjects had a greater decrease in HDL-C than
did male subjects (19.4% vs 11.6%) in response to a high-
complex-carbohydrate, high-fiber, low-fat, and low-cholesterol
diet (49). Jenkins et al (50) also reported that men were more
responsive than women to a diet high in soluble fiber compared
with a diet high in insoluble fiber (both diets were low in
saturated fat); men had a significantly greater reduction in total
cholesterol (7.5% vs 3.4%) and LDL-C (9.6% vs 2.2%). Like-
wise, Zock and Katan (18) found that a diet high in steanic acid
resulted in a larger decrease in total cholesterol and LDL-C in
men than in women. Taken together, all of these studies sug-
gested that total cholesterol and LDL-C are more responsive to
diet in men whereas HDL-C appears to be more responsive in
women. In contrast, Mensink and Katan (10, 1 1) reported a
greater change in HDL in men than in women when SFAS were
removed from the diet.
The apparent sex differences in dietary responsiveness are
intriguing. It is important to note that few investigations have
been conducted to specifically examine dietary responsiveness
in women and men. Nonetheless, although some consistent
differences have been observed between sexes, it is premature
to define the actual diet-sex effects (and differences) on lipids
and lipoproteins. Clearly, although the results of the present
investigation indicate similar effects of diet on total cholesterol
and LDL-C in women and men, further studies are needed to
corroborate these findings, especially because of the inconsis-
tencies reported among other studies. Moreover, because of the
importance of HDL-C as a risk factor for coronary heart
disease for both women and men (51, 52), additional studies
are needed to understand how diet and sex affect HDL-C
concentrations and metabolism.
at PE
NN
SY
LVA
NIA
ST
AT
E U
NIV
PA
TE
RN
O LIB
RA
RY
on February 21, 2013
ajcn.nutrition.orgD
ownloaded from
1138 YU El AL
32. Bonanome A, Grundy SM. Effect of dietary stearic acid on plasma
cholesterol and lipoprotein levels. N Engl I Med 1988;318:124’4-8.
Summary
In summary, the blood cholesterol predictive equations pre-
sented herein indicate that SFAS (specifically 12:0, 14:0, and
16:0) significantly increase total cholesterol, LDL-C, and
HDL-C concentrations. Steanic acid, in contrast, is a unique
long-chain SFA and does not increase plasma total cholesterol
and LDL-cholestenol concentrations. Because of this we pro-
pose that it be distinguished from the other long-chain SFAS in
plasma cholesterol predictive equations. We believe this isparticularly important given that many investigations group all
of the long-chain SFAs together. Further studies are needed tocorroborate the observation that steanic acid may decrease
HDL-C concentrations in women. PUFAS and MUFAs signif-
icantly decrease total cholesterol and LDL-C concentrations;
PUFAs do not decrease HDL-C concentrations whereas MU-
FAs may increase them. MUFAs elicit less potent cholesterol-
lowering effects compared with PUFAS. We propose that the
variable cholesterolemic effects observed for MUFAs previ-
ously are explained by the relatively high amount of 12:0-16:0
SFAs in the diet, which appears to obscure the MUFA re-
sponse. The predictive equations for men and women indicate
that the total cholesterol and LDL-C responses to diet are
similar for both sexes. Of potential significance is the evidence
that suggests there is a sex difference in responsiveness of
HDL-C to diet. U
References
1 . Keys A, Anderson IT, Grande F. Serum cholesterol response to
changes in the diet: IV. Particular saturated fatty acids in the diet.
Metabolism 1965; 14:776-87.
2. Keys A, Anderson IT, Grande F. Prediction of serum-cholesterol
responses of man to changes in fats in the diet. Lancet 1957;2:959-66.
3. Hegsted DM, McGandy RB, Myers ML, Stare Fl. Quantitative effects
of dietary fat on serum cholesterol in man. Am I Clin Nutr 1965;17:
281-95.
4. Mensink RP, Katan MB. Effect of dietary fatty acids on serum lipids
and lipoproteins: a meta-analysis of 27 trials. Arterioscler Thromb
1992;12:91 1-9.
5. Hegsted DM, Ausman LM, Johnson IA, Dallal GE. Dietary fat and
serum lipids: an evaluation of the experimental data. Am I Clin Nutr
1993;57:875-83.
6. Derr I, Kris-Etherton PM, Pearson TA, Seligson FH. The role of fatty
acid saturation on plasma lipids, lipoproteins, and apolipoproteins: II.
The plasma total and low-density lipoprotein cholesterol response of
individual fatty acids. Metabolism 1993;42:130-4.
7. Berry EM, Eisenberg 5, Haratz D, et al. Effects of diets rich in
monounsaturated fatty acids on plasma lipoproteins-the Jerusalem
Nutrition Study: high MUFA.S vs high PUFAS. Am I Clin Nutr
1991;53:899-907.
8. Grundy SM. Comparison of monounsaturated fatty acids and carbo-
hydrates for lowering plasma cholesterol. N Engl I Med 1986;314:
745-8.
9. Grundy SM, Florentin L, Nix D, Whelan MF. Comparison of monoun-
saturated fatty acids and carbohydrates for reducing raised levels of
plasma cholesterol in man. Am I Clin Nutr 1988;47:965-9.
10. Mensink RP, Katan MB. Effect of a diet enriched with monounsat-
urated or polyunsaturated fatty acids on levels of low-density and
high-density lipoprotein cholesterol in heathy men and women. N Engl
I Med 1989;321:436-41.
I I . Mensink RP, Katan MB. Effect of monounsaturated fatty acids versus
complex carbohydrates on high-density lipoproteins in healthy men
and women. Lancet 1987;1:122-5.
12. Ginsberg HN, Barr SL, Gilbert A, et al. Reduction of plasma choles-
terol levels in normal men on an American Heart Association step 1
diet or a step 1 diet with added monounsaturated fat. N Engl I Med
1990;322:574-9.
13. Harris WS, Connor WE, McMurry MP. The comparative reductions of
the plasma lipids and lipoproteins by dietary polyunsaturated fats:
salmon oil versus vegetable oils. Metabolism l983;32:179-84.
14. McDonald BE, Gerrard IM, Bruce VM, Corner U. Comparison of the
effect of canola oil and sunflower oil on plasma lipids and lipoproteins
and on in vivo thromboxane A, and prostacyclin production in healthy
young men. Am I Clin Nutr 1989;50:1382-8.
15. Mensink RP, Katan MB. Effect of dietary trans fatty acids on high-
density and low-density lipoprotein cholesterol levels in healthy sub-
jects. N Engl I Med 1990;323:439-45.
16. Friday KE, Failor RA, Childs MT. Bierman EL. Effects of n-3 and
n-6 fatty acid-enriched diets on plasma lipoproteins and apolipopro-
teins in heterozygous familial hypercholesterolemia. Arterioscler
Thromb 1991;! 1:47-54.
17. Nestel P, Noakes M, Belling GB, McArthur R, Clifton PM, Abbey M.
Plasma cholesterol-lowering potential of edible-oil blends suitable for
commercial use. Am I Clin Nutr 1992;55:46-50.
18. Zock PL, Katan MB. Hydrogenation alternative: effects of trans fatty
acids and stearic acid versus linoleic acid on serum lipids and lipopro-
teins in humans. I Lipid Res 1992;33:399-410.
19. Mata P, Garrido IA, Ordovas IM, et al. Effect of dietary monounsat-
urated fatty acids on plasma lipoproteins and apolipoproteins in
women. Am I Clin Nutr 1992;56:77-83.
20. Mensink RP, Zock PL, Katan MB, Hornstra G. Effect of dietary cis
and trans fatty acids on serum lipoprotein[a] levels in humans. I Lipid
Res 1992;33: 1493-501.
21. Barr SL, Ramakrishnan R, Johnson C, Holleran, Dell RB, Ginsberg
HN. Reducing total dietary fat without reducing saturated fatty acids
does not significantly lower total plasma cholesterol concentrations in
normal males. Am I Clin Nutr 1992;55:675-81.
22. Ng TKW, Hayes KC, DeWitt GF, et al. Dietary palmitic and oleic
acids exert similar effects on serum cholesterol and lipoprotein profiles
in normocholesterolemic men and women. I Am Coll Nutr 1992;l 1:
383-90.23. Nestel P, Noakes M, Belling B, et al. Plasma lipoprotein lipid and
Lp[a] changes with substitution of elaidic acid for oleic acid in the diet.
I Lipid Res 1992;33:1029-36.
24. Kris-Etherton PM, Derr I, Mitchell DC, et al. The effect of fatty acid
saturation on plasma lipids, lipoproteins, and apolipoproteins: I. effects
of whole-food diets high in cocoa butter, olive oil, soybean oil, dairy
butter, and milk chocolate on the plasma lipids of young men. Metab-
olism 1993;42:121-9.
25. Sabat#{233}I, Fraser GE, Burke K, Knutsen SF, Bennett H, Lindsted KD.
Effects of walnuts on serum lipid levels and blood pressure in normal
men. N Engl I Med 1993;328:603-7.
26. Grande F, Anderson IT, Keys A. Comparison of effects of palmitic
acid and stearic acid in the diet on serum cholesterol in men. Am I Clin
Nutr 1970;23:1 184-93.
27. Brussaard IH, Katan MB, Groot PHE, Havekes LM, Hautvast 1GM.
Serum lipoprotein of healthy persons fed a low-fat diet or a polyun-
saturated fat diet for three months. Atherosclerosis 1982;42:205-19.
28. Hegsted DM, Nicolosi RI. Do formula diets attenuate the serum
cholesterol response to dietary fats? I Vasc Med Biol 1990;2:69-73.
29. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concen-
tration of low-density lipoprotein in plasma, without use of the pre-
parative ultracentrifuge. Clin Chem 1972;18:499-502.
30. SAS Institute. SAS user’s guide: basics. Version 5. Cary, NC: SAS
Institute Inc.
31. Denke MA, Grundy SM. Effects of fats high in stearic acid on lipid
and lipoprotein concentrations in men. Am I Clin Nutr 1991;54: 1036-
40.
at PE
NN
SY
LVA
NIA
ST
AT
E U
NIV
PA
TE
RN
O LIB
RA
RY
on February 21, 2013
ajcn.nutrition.orgD
ownloaded from
CHOLESTEROLEMIC EFFECTS OF 18:0 AND MUFA 1139
33. Becker N, Illingworth DR. Alaupovic P, Connor WE, Sundberg EE.
Effects of saturated, monounsaturated, and w-6 polyunsaturated fatty
acids on plasma lipids, lipoproteins, and apoproteins in humans. Am I
Clin Nutr 1983;37:355-60.
34. Spady DK, Woollett LA, Dietschy JM. Regulation of plasma LDL-
cholesterol levels by dietary cholesterol and fatty acids. Annu Rev
Nutr 1993;13:355-81.
35. Dietschy IM, Woollett LA, Spady DK. The interaction of dietary
cholesterol and specific fatty acids in the regulation of LDL receptor
activity and plasma LDL-cholesterol concentrations. Ann N Y Acad
Sci l993;676:l 1-26.
36. Mattson FH, Grundy SM. Comparison of effects of dietary saturated,
monounsaturated, and polyunsaturated fatty acids on plasma lipids and
lipoproteins in man. I Lipid Res 1985;26:194-202.
37. Gustafsson lB. Vessby B, Nydahl M. Effects of lipid-lowering diets
enriched with monounsaturated and polyunsaturated fatty acids on
serum lipoprotein composition in patients with hyperlipoproteinaemia.
Atherosclerosis 1992;96: 109-18.
38. Mata P, Alvare-Sala LA, Rubio Ml, Nu#{241}o1, Oya MD. Effects of
long-term monounsaturated- vs polyunsaturated- enriched diets on
lipoproteins in healthy men and women. Am I Clin Nutr 1992;55:846-
50.
39. Hashim SA, Arteaga A, Van Itallie TB. Effect of a saturated medium-
chain triglyceride on serum-lipids in man. Lancet 1960;1:1105-8.
40. Denke MA, Grundy SM. Comparison of effects of lauric acid and
palmitic acid on plasma lipids and lipoproteins. Am I Clin Nutr
1992;56:895-8.
41. Hayes KC, Khosla P. Dietary fatty acid thresholds and cholesterol-
emia. FASEB I 1992;6:2600-7.
42. Zock PL, Vries JHM, Katan MB. Impact of myristic acid versus
palmitic acid on serum lipid and lipoprotein levels in healthy women
and men. Arterioscler Thromb 1994;14:567-75.
43. Vega GL, Groszek E, Wolf R, Grundy SM. Influence of polyunsatu-
rated fats on composition of plasma lipoproteins and apolipoproteins.
I Lipid Res 1982;23:81 1-22.
44. Schaefer El, Levy RI, Ernst ND, Van Sant FD, Brewer HB Jr. The
effects of low cholesterol, high polyunsaturated fat, and low fat diets
on plasma lipid and lipoprotein cholesterol levels in normal and
hypercholesterolemic subjects. Am I Clin Nutr 1981;34:1758-63.
45. Shepherd I, Packard Ci, Grundy SM, Yeshurun D, Gotto AM Ir,
Taunton OD. Effects of saturated and polyunsaturated fat diets on the
chemical composition and metabolism of low density lipoproteins in
man. I Lipid Res 1980;21:91-9.
46. Erickson BA, Coots RH, Mattson FH, Kiigman AM. The effect of
partial hydrogenation of dietary fats, of the ratio of polyunsaturated to
saturated fatty acids, and of dietary cholesterol upon plasma lipids in
man. I Clin Invest l964;43:20l7-25.
47. Gustafsson IB, Vessby B, Karlstrom B, Boberg I, Boberg M, Lithell H.
Effects on the serum lipoprotein concentrations by lipid-lowering diets
with different fatty acid compositions. I Am Coil Nutr 1985;4:241-8.
48. Clifton PM, Nestel P1. Influence of gender, body mass index, and age
on response of plasma lipids to dietary fat plus cholesterol. Arterio-
scler Thromb 1992;12:955-62.
49. Barnard Ri. Effects of life-style modification on serum lipids. Arch
Intern Med 1991;151:1389-94.
50. Jenkins DIA, Wolever TMS, Rao AV, et al. Effect on blood lipids of
very high intakes of fiber in diets low in saturated fat and cholesterol.
N EngI I Med 1993;329:21-6.
51. Jacobs DR Jr, Mebane IL, Bangdiwala SI, Criqui MH, Tyroler HA.
High density lipoprotein cholesterol as a predictor of cardiovascular
disease mortality in men and women: the follow-up study of the lipid
research clinics prevalence study. Am I Epidemiol 1990;131:32-47.
52. Castelli WP, Doyle IT, Gordon T, Ct al. HDL cholesterol and other
lipids in coronary heart disease. Circulation 1977;55:767-72.
at PE
NN
SY
LVA
NIA
ST
AT
E U
NIV
PA
TE
RN
O LIB
RA
RY
on February 21, 2013
ajcn.nutrition.orgD
ownloaded from