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,2
* Department of Nutritional Sciences,
The Huck Institutes of the Life Sciences, and
** Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA
2To whom correspondence should be addressed. E-mail: kfc107{at}psu.edu.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • inflammation • cholesterol • diet • isoflavones • hormone replacement therapy
Chronic inflammation is a major contributor to atherosclerosis 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 hepatocytes in response to proinflammatory cytokines such as interleukin (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 responsive to a cholesterol-lowering diet (12). In an ancillary study of the Dietary Approaches of Stop Hypertension (DASH)-Sodium 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 hypothesis.
Soy protein has been recommended for cholesterol lowering (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 hormone replacement therapy (HRT) had different lipid responses to a blood cholesterol-lowering diet than men and untreated postmenopausal women (14). Men and unmedicated 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 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.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Participants. 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 analyses. 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.
Biochemical assays. 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 concentrations 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 (Strategic Diagnostics).
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 calculated 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 
2 analyses 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 analysis was used to examine the strength of the relations among inflammation, 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.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Effects of CRP status on lipid response to diet.
We 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 magnitude 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, respectively).
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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 R2 for 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 for all).
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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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-cholesterol 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 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 responsiveness.
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 infection; 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 stimulator 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 metabolism. 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 considered 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 attenuated 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 observed in previous studies of overweight/obese subjects. Further 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 simultaneously. 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 estrogens on CRP, it also is important to test whether consumption 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.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: apo, apolipoprotein; C, cholesterol; CRP, C-reactive protein; DASH, Dietary Approaches to Stop Hypertension; HRT, hormone replacement therapy; IL, interleukin; IQR, interquartile range; Lp(a), lipoprotein(a); TC, total cholesterol; TG, triglyceride.
Manuscript received 20 January 2005. Initial review completed 14 February 2005. Revision accepted 25 February 2005.
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