Human Nutrition and Metabolism
Lipid Response to a Low-Fat Diet with or without Soy Is Modified by
C-Reactive Protein Status in Moderately Hypercholesterolemic Adults1
Kirsten F. Hilpert,*†2Penny M. Kris-Etherton,* and Sheila G. West**
*Department of Nutritional Sciences,†The Huck Institutes of the Life Sciences, and **Department of
Biobehavioral Health, The Pennsylvania State University, University Park, PA
marker of inflammation, are less responsive to cholesterol-lowering diets. CRP concentrations are increased by
oral estrogen; however, the effect of soy phytoestrogens on inflammation has not been studied comprehensively,
especially in women receiving hormone replacement therapy (HRT). This study was conducted to determine
whether adding soy to a low-fat, high-fiber diet affects CRP and interleukin (IL)-6, and to examine the association
between CRP levels and lipid response in moderately hypercholesterolemic adults (men ? 18, postmenopausal
women ? 14; 6 receiving HRT). After a 3-wk run-in period with consumption of a Step I diet (27% total fat, 7%
saturated fat, 275 mg cholesterol), participants were randomly assigned to diets containing 25 g/d soy protein
(? 90 mg/d isoflavones) or 25 g/d milk protein for 6 wk in a crossover design. Lipids and lipoproteins, CRP, and
IL-6 were measured at the end of each diet and participants were categorized into high (?3.5 mg/L) or low CRP
groups based on a median split. The addition of soy or milk protein to the Step I diet did not affect lipids or
inflammatory markers. Regardless of protein source, those with low CRP exhibited significant decreases in LDL
cholesterol (?3.5%) and the LDL:HDL cholesterol ratio (?4.8%), whereas those with high CRP had significant
increases in LDL cholesterol (?4.8%), the LDL:HDL cholesterol ratio (?5.2%), apolipoprotein B (?3.8%), and
lipoprotein(a) (?13.5%) compared with the run-in diet. These results suggest that inflammation may not only
attenuate lipid responses, but also aggravate dyslipidemia in hypercholesterolemic subjects consuming a choles-
terol-lowering diet. J. Nutr. 135: 1075–1079, 2005.
Recent evidence suggests that individuals with high concentrations of C-reactive protein (CRP), a
● inflammation ● cholesterol ● diet ● isoflavones ● hormone replacement therapy
Chronic inflammation is a major contributor to atheroscle-
rosis and cardiovascular disease (1). An important marker of
inflammation is an elevation in serum C-reactive protein
(CRP)3(2–4), an acute-phase reactant secreted by hepato-
cytes in response to proinflammatory cytokines such as inter-
leukin (IL)-6. In several large epidemiologic studies, CRP was
shown to be a strong, independent predictor of CVD risk in
both men and women (5–8).
The mechanism by which inflammation increases CVD risk
is not known. However, it is possible that inflammation may
adversely affect lipid metabolism. During periods of acute
inflammation, lipid metabolism is altered to reflect a
proatherogenic profile [including increased triglycerides (TG),
decreased HDL cholesterol (HDL-C), and the appearance of
small, dense LDL particles] (9–11). A recent study reported
that subjects with high CRP concentrations were less respon-
sive to a cholesterol-lowering diet (12). In an ancillary study of
the Dietary Approaches of Stop Hypertension (DASH)-So-
dium trial, Erlinger et al. (12) showed that baseline CRP levels
were strongly associated with lipid response to a cholesterol-
lowering diet. Only individuals with low CRP levels (?2.37
mg/L) experienced a significant reduction in total cholesterol
(TC) and LDL cholesterol (LDL-C) (?9.8%, P ? 0.0001 and
?11.8%, P ? 0.0001, respectively) when consuming the
DASH diet, whereas their TG remained unchanged. The
opposite pattern was observed in the high CRP group; TC and
LDL-C did not change and TG increased significantly
(?19.8%, P ? 0.0001). Taken together, these studies suggest
that inflammation may aggravate lipid abnormalities (9–11)
and may attenuate the effectiveness of dietary interventions
(12). Few studies, however, have directly tested this hypoth-
Soy protein has been recommended for cholesterol lower-
ing (13); however, several recent studies, including our own
(14), did not observe lipid-lowering effects of soy protein
(15–18). Postmenopausal women who were receiving hor-
mone replacement therapy (HRT) had different lipid re-
sponses to a blood cholesterol-lowering diet than men and
untreated postmenopausal women (14). Men and unmedi-
cated women had significant reductions in TC (?17.3%) and
LDL-C (?16.6%) when consuming a Step I diet, whereas
HRT-treated women did not. The reason for the differential
1Primary funding was provided by grants from Protein Technologies Inter-
national (now the Solae Company), and services were provided by the General
Clinical Research Center of The Pennsylvania State University (National Institutes
of Health #M01RR10732).
2To whom correspondence should be addressed. E-mail: firstname.lastname@example.org.
3Abbreviations used: apo, apolipoprotein; C, cholesterol; CRP, C-reactive
protein; DASH, Dietary Approaches to Stop Hypertension; HRT, hormone re-
placement therapy; IL, interleukin; IQR, interquartile range; Lp(a), lipoprotein(a);
TC, total cholesterol; TG, triglyceride.
0022-3166/05 $8.00 © 2005 American Society for Nutritional Sciences.
Manuscript received 20 January 2005. Initial review completed 14 February 2005. Revision accepted 25 February 2005.
by guest on June 1, 2013
responsiveness in HRT-treated women is not clear. The use of
HRT in postmenopausal women has been associated with
increased CRP (19). In the present study, we hypothesized
that HRT-treated women would have higher levels of CRP,
and that this may explain their differential lipid response to a
cholesterol-lowering diet. The primary aims of the present
study were to examine the association between soy intake and
levels of inflammatory markers in HRT-treated and untreated
women, and men and to determine whether CRP status affects
lipid responses to a cholesterol-lowering Step I diet.
SUBJECTS AND METHODS
Serum concentrations of CRP, IL-6, and lipids and lipoproteins
were measured in 32 subjects who participated in a controlled feeding
study designed to examine the effects of soy protein on the lipid and
lipoprotein profile. Details of this randomized, placebo-controlled,
crossover design were reported previously (14).
All participants were nonsmokers and in good
health. They had TC ? 5.27 mmol/L, LDL-C levels above the 50th
percentile, and TG below the 90th percentile according to NHANES
III norms (20). None were taking cholesterol-lowering medications.
Fourteen men and 18 postmenopausal women completed the study in
full compliance. The sample included 12 women who were not taking
postmenopausal hormones and 6 who were taking Prempro (0.625
mg/d conjugated equine estrogens, plus 2.5 mg/d medroxyprogestrone
acetate by Wyeth Pharmaceuticals). One woman taking raloxifene, a
selective estrogen receptor modulator, was excluded from the analy-
ses. The protocol was approved by the Biomedical Committee of the
Institutional Review Board at The Pennsylvania State University,
and written informed consent was obtained from all participants.
Experimental diets. Throughout the 17-wk study, all meals and
snacks were prepared in a metabolic kitchen and were provided for
outpatient consumption. After a 3-wk run-in period while consuming
the National Cholesterol Education Program Step I diet (27% total
fat, 7% saturated fat, 275 mg cholesterol, 55% carbohydrate, 20.5 g/d
insoluble fiber, 8.4 g/d soluble fiber), participants were immediately
randomly assigned to 6 wk of a Step I diet containing 25 g/d soy
protein isolate ? 90 mg/d isoflavones or 25 g/d milk protein isolate
(14). After a 2-wk compliance break in which participants consumed
their habitual diet, participants crossed over to the other treatment
for the final 6 wk. Blood samples were collected from fasting subjects
on 2 consecutive days at the end of the run-in period and at the end
of each of the 2 diet periods according to a standardized protocol.
Aliquots were stored at ?80°C until the end of the study, when all
samples were analyzed. Concentrations of TC, LDL-C, HDL-C, TG,
and apolipoproteins (apo) are reported as the mean value over 2 d of
testing, whereas concentrations of CRP and IL-6 were measured using
samples from the first day’s blood draw.
IL-6 and CRP were measured by ELISA
developed by the Cytokine Core Laboratory of the Pennsylvania
State General Clinical Research Center, and described previously by
us (21). The CV for both assays was ?6.0%.
Serum concentrations of TC, HDL-C, and TG were determined
by enzymatic assays as previously described (14) at the Mary Imogene
Bassett Research Institute. HDL-C was determined after precipitation
of apo B-containing lipoproteins with dextran sulfate. LDL-C con-
centrations were calculated by the Friedewald equation. Non-HDL-C
was calculated as TC minus HDL-C. Rate immunonephelometry was
used to measure apo B and apo A-1 (Beckman Array; Beckman
Instruments), and lipoprotein(a) [Lp(a)] was determined by ELISA
Statistical analysis. Primary analyses were performed using the
mixed models procedure in SAS (version 8.2; SAS Institute). Values
are presented as least squares means ? SEM unless otherwise noted.
The distributions for CRP and IL-6 were corrected with natural log
transformations, and the untransformed data are presented as medians
with interquartile ranges [median (IQR)].
Consistent with the study conducted by Erlinger et al. (12),
subjects with a mean CRP concentration greater than the median
were classified as high CRP (n ? 16) and those below the median
were classified as low CRP (n ? 16). Because CRP levels fluctuate
(22), we took a conservative approach in determining the median.
Because there was no effect of diet on CRP, we calculated the mean
of the 3 treatment values for CRP for each subject, and then calcu-
lated the median of the entire sample [3.5 mg/L (1.5, 5.8)]. Only 17
subjects had detectable serum concentrations of IL-6 and statistical
analysis of IL-6 was limited to this population. The sample size for
each analysis is indicated in the table.
Both t tests and ?2analyses were used to test whether any of the
demographic or cardiovascular health variables differed between the
high and low CRP groups. To investigate potential inflammation-
related differences in lipid response to a cholesterol-lowering diet, the
change in each lipid and lipoprotein variable was calculated as the
difference between the run-in and end-of-diet levels for each variable.
The model included diet (soy vs. milk protein), CRP group, order of
diet presentation, and their interactions. Covariates included BMI,
fasting values of each parameter at the end of the run-in period, and
changes in body weight over the course of the study. Body weight
changes were small (a mean of 0.6 kg) and did not differ between
CRP groups. For all analyses, significant main effects (P ? 0.05) were
investigated using the Tukey-Kramer test. Stepwise regression anal-
ysis was used to examine the strength of the relations among inflam-
mation, BMI, and diet-induced lipid changes. A significant increase
in R2(P ? 0.05) with the addition of a variable was considered
significant in the regression equation.
At the end of the 3-wk run-in period, the high CRP group
had higher TG and BMI levels (P ? 0.01) (Table 1). Lipid
and lipoprotein concentrations did not differ between the
groups. Of the 6 women receiving HRT, 4 (67%) were in the
high CRP group.
Effects of diet and hormone status on inflammatory mark-
CRP and IL-6 concentrations did not differ between
groups, suggesting that soy, in the context of a Step I diet, did
not affect these inflammatory markers [CRP: 4.2 mg/L (1.2,
6.4), 2.7 mg/L (0.9, 5.2), and 3.3 mg/L (1.4, 5.7); IL-6: 99.4
ng/L (42.4, 321.5), 61.6 ng/L (43.9, 554.6), and 99.4 ng/L
(30.4, 517.6) following run-in, soy, and milk, respectively]. In
agreement with several previous studies, we found that median
CRP levels in women receiving HRT were significantly higher
than the median CRP in men [5.8 mg/L (3.0, 9.5) vs. 2.9 mg/L
(1.2, 4.5), respectively, Tukey adjusted P ? 0.02]. The median
CRP concentrations of the group of women not receiving
HRT [3.4 mg/L (1.6, 6.0)] were intermediate and did not differ
from those of women receiving HRT or men. As reported
previously, effects on lipids and lipoproteins did not differ
among the 3 diets (14).
Effects of CRP status on lipid response to diet.
examined whether subjects who differed in their levels of CRP
had different lipid responses to the soy and milk protein diets
(Fig. 1). The CRP groups differed in the direction and mag-
nitude of changes in LDL-C, non-HDL-C, the LDL:HDL
cholesterol ratio, apo B, and Lp(a) during continued exposure
to a Step I diet. There were significant effects of CRP group for
each of these variables (P ? 0.05). During continued exposure
to the low-fat diets, the high CRP group had significant
increases in atherogenic lipids, whereas the low CRP group
had the opposite pattern. In contrast, group differences in TC
and the total:HDL cholesterol ratio response to diet did not
differ after controlling for BMI. In addition, diet-related
changes in HDL-C, apo A-1, and TG were not influenced by
CRP status (high vs. low CRP; ?0.01 ? 0.02 vs. 0.02 ? 0.02
mmol/L, P ? 0.45; ?2.01 ? 2.36 vs. 2.96 ? 2.36 mg/L, P
? 0.17; 0.11 ? 0.06 vs. 0.02 ? 0.06 mmol/L, P ? 0.64,
In both groups of subjects, CRP and IL-6 levels remained
HILPERT ET AL.
by guest on June 1, 2013
unchanged throughout the study. Median changes in CRP
[?0.15 (?1.57, 1.83) vs. ?0.18 (?1.01, 0.73) mg/L, P
? 0.69)] and IL-6 [19 (?3.6, 10.7) vs. 82 (?8.8, 124.9) ng/L,
P ? 0.94] did not differ between the high and low CRP groups.
Identification of predictors of LDL response to diet. To
examine whether CRP status was an independent predictor of
the response of LDL-C to diets, we used stepwise multiple
regression. The model included the change in LDL-C as the
dependent variable; the independent variables included BMI,
LDL-C, and TG values at run-in, CRP group, order of diet
presentation, subgroup, age, and changes in weight. CRP
group alone explained 37% (P ? 0.0003) of the variance in
the change in LDL-C, whereas the run-in level of LDL-C
explained an additional 8% of the variance in lipid response to
diet. The combined R2for the change in LDL-C was 0.45 (P
? 0.0002). CRP levels and fasting TG were directly correlated
during each diet period (Spearman r ? 0.40 for all, P ? 0.02
The present study provides additional evidence that CRP
status influences lipid response to a cholesterol-lowering diet.
In this study, a Step I diet lowered LDL-C and the ratio of
LDL:HDL cholesterol only in subjects with CRP levels below
the sample median (3.5 mg/L). Surprisingly, those with CRP
levels higher than the median had significant increases in these
atherogenic lipids along with apo B and Lp(a) while consum-
ing a Step I diet. The addition of soy protein or milk protein
to the Step I diet did not affect the lipid profile or inflamma-
tory markers we measured. These results suggest that habitual
consumption of a Step I diet may beneficially affect individuals
with CRP levels ? 3.5 mg/L and may have deleterious effects
in patients with elevated levels. It is important to point out
that some of the subjects (n ? 11) in our “low” CRP group had
higher than optimal levels of CRP (?1.0 mg/L) (23). This
may reflect our study cohort of older, overweight, hypercho-
The results of the present study are similar to those reported
by Erlinger et al. (12) who found that LDL-C decreased
significantly after 12 wk of consuming a low-fat, low-choles-
terol diet only in people with basal CRP ? 2.37 mg/L. After
4 wk of consuming this diet, individuals with CRP levels
? 2.37 mg/L experienced slight decreases in TC and LDL-C;
however, the concentrations of these lipids started to increase
at 8 wk and continued to return to or surpass baseline levels at
12 wk. The TC and LDL-C concentrations, although not
significantly different from baseline, followed a pattern similar
to the one observed in the present study. Erlinger et al. (12)
also found a significant increase in TG only in those with
elevated CRP. In the present study, TG increased the most in
the high CRP group; however, this group difference in TG
Subject characteristics at the end of the 3-wk run-in period by CRP status1,2
High CRP group
(n ? 16)
Low CRP group
(n ? 16)
(n ? 32)
% women taking HRT
Apo B, mg/L
Apo A-1, mg/L
59.12 ? 1.25
27.35 ? 0.77a
79.24 ? 2.88
56.82 ? 1.26
24.97 ? 0.77
75.05 ? 2.89
57.97 ? 0.93
26.16 ? 0.55
77.14 ? 1.96
5.8 (4.6, 6.7)*
76 (45, 263)
5.49 ? 0.17
3.57 ? 0.13
1.19 ? 0.07
1.58 ? 0.12*
4.30 ? 0.15
3.14 ? 0.23
4.78 ? 0.27
114.53 ? 4.30
150.22 ? 8.06
19.62 ? 5.46
1.6 (1.0, 2.5)
119 (42, 509)
5.52 ? 0.17
3.80 ? 0.13
1.19 ? 0.07
1.17 ? 0.13
4.33 ? 0.15
3.32 ? 0.22
4.79 ? 0.26
117.22 ? 4.24
143.91 ? 7.93
21.57 ? 4.95
3.6 (1.6, 5.8)
99 (42, 322)
5.49 ? 0.12
3.68 ? 0.09
1.19 ? 0.05
1.36 ? 0.09
4.30 ? 0.11
3.23 ? 0.15
4.78 ? 0.18
115.59 ? 2.26
146.95 ? 5.34
21.18 ? 3.72
1Values are least-squares means ? SEM (range) unless otherwise indicated. *Different from low CRP, P ? 0.01.
2CRP status defined as high (?3.5 mg/L) or low (?3.5 mg/L) based on a median split.
3Because of skewed distributions, medians and interquartile ranges are presented for CRP and IL-6.
4n ? 7 (high CRP) and 10 (low CRP).
the end of the run-in period in subjects with high (?3.5 mg/L, n ? 16)
and low (?3.5 mg/L, n ? 16) CRP. The changes are least-square means
? SEM, n ? 32. The CRP group is defined by a median split. The
P-values define the effect of CRP group, collapsing across both diets.
*Different from run-in level overall, collapsing across both diets, P
The percentage change in lipids and lipoproteins from
DIET RESPONSE AND CRP
by guest on June 1, 2013
response was not significant. Taken together, these 2 studies
point to a biological mechanism (i.e., inflammation) that may
explain some of the individual variation in diet responsive-
The mechanism by which elevated CRP interferes with
lipid response to diet is not clear. Inflammation was shown to
decrease HDL-C, and increase TG levels due to increased
production of VLDL (9). LDL-C usually decreases with infec-
tion; however, the particles become small and dense and thus
more atherogenic in nature (10,11). These lipid changes can
be attributed to cytokine activity (24). IL-6, a potent stimu-
lator of CRP, induces de novo fatty acid synthesis and lipolysis,
which increase circulating levels of FFA that subsequently lead
to increased hepatic VLDL secretion (25). In vivo and cell
culture work by Greenberg et al. (26) also suggests that IL-6
decreases lipoprotein lipase activity in adipose tissue, thus
decreasing the clearance of TG-rich lipoproteins. Little is
known regarding the direct effects of CRP on lipid metabo-
lism. Because CRP can bind TG-rich and apo-B–containing
particles, the interaction of CRP and plasma lipoproteins may
have important metabolic consequences (27–30). Research
examining whether a chronic state of inflammation modifies
diet-induced changes in lipids is sparse (12,21).
In the present study, women receiving HRT had a 2-fold
higher CRP level than men. This is in agreement with other
studies (19,31–33). This increase in CRP may be related to the
increased risk of CVD in women taking HRT observed in the
Heart and Estrogen/Progestin Replacement study (34) and
Women’s Health Initiative study (35). Because of the close
association between HRT use and inflammation, we consid-
ered whether the patterns we attributed to CRP status actually
reflected the effects of exogenous hormone use. However,
inclusion of this factor in the mixed model analyses did not
alter the results, and hormone use was never a significant
predictor in the regression analyses. Furthermore, the same
patterns also were observed within the group of men and
unmedicated women, suggesting that inflammation, and not
hormone use, was the primary factor driving this effect.
An association between BMI and dyslipidemia was reported
in men and women. Excess body weight is associated with
higher TG, TC, non-HDL-C, and LDL-C levels, and lower
HDL-C levels (36). In fact, several reports showed an atten-
uated lipid response to dietary intervention in overweight
subjects (37,38). Body weight is also a critical source of CRP
variation (39,40). Therefore, it is possible that overweight
individuals, who have higher CRP levels, will respond less
favorably to dietary changes (41). To further explore the
complexity of diet responsiveness, we performed regression
analyses. These analyses showed that CRP group was the best
predictor of change in LDL-C, even when BMI and change in
bodyweight were included as factors in the model, suggesting
that CRP status, which is positively associated with BMI, may
be an underlying cause of the attenuated diet response ob-
served in previous studies of overweight/obese subjects. Fur-
ther research is required to distinguish between inflammation
and obesity as the underlying causative factor. Due to the
direct association between adiposity and CRP, the issue is
further complicated when weight loss is occurring simulta-
neously. Because of the tight link between weight change and
CRP, controlled metabolic studies remain the most important
research design for studying these effects.
Given the concern about adverse effects of exogenous es-
trogens on CRP, it also is important to test whether consump-
tion of soy phytoestrogens increases inflammation, especially
in women receiving HRT. In a group of 23 men and 18
postmenopausal women, 5 of whom were receiving HRT,
Jenkins et al. (42) found no change in CRP concentrations
during consumption of a soy protein diet containing either 10
or 73 mg/d of isoflavones. However, women experienced
higher levels of IL-6 during the high-isoflavone diet compared
with a dairy food control phase, but not compared with the
low-isoflavone diet. The researchers did not report differences
according to HRT status. Furthermore, recent studies show
that low-dose vs. standard-dose estrogen replacement does not
elicit the same CRP increases in postmenopausal women (43).
The results of our study are consistent with those of Jenkins et
al. (42) and extend them to suggest that a Step I diet with soy
does not affect levels of CRP in subjects with high basal levels.
The results of the present study strongly imply that we
should be treating inflammation to realize the full benefits of a
blood cholesterol-lowering diet. Yet little is known about the
effect of diet on CRP levels (21,44–48). Recently, a low-fat
vegetarian diet, which included high-fiber foods, plant sterols,
soy protein, and almonds, reduced CRP levels 28%, which was
comparable to the effect of statin drugs (49). We also showed
that a diet high in plant-based (n-3) fatty acids significantly
reduced CRP by 75% (21). Interventions that target multiple
CVD risk factors are expected to have the greatest effect on
reducing risk. The results of the present study provide a further
impetus for this research.
We appreciate technical assistance provided by Christina Mack
who performed the assays for CRP and IL-6.
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