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Lipid Laboratory (LIM10), University of São Paulo Medical School, São Paulo Brazil;
* INSERM U498, Laboratoire de Biochimie Médicale, Hôpital du Bocage, Dijon, France; and
University of São Paulo Medical School, Ribeirão Preto, Brazil
2To whom correspondence should be addressed. E-mail: lipideq{at}usp.br.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • plasma lipoproteins • cholesteryl ester transfer protein polymorphism • plant sterol ester • apoE polymorphism.
Dietary modifications such as the addition of naturally occurring plant sterols (PSE) are known to lower plasma cholesterol concentration in humans and experimental animals (1–8). In humans, intakes of 
2 g/d of plant sterols achieve this effect without modification of the concentrations of HDL cholesterol (HDL-C) and triacylglycerols (TG) (2–4). These results led to the enrichment of commercially available margarines with esters of plant sterols or stanols (5–9). In addition, the safety and tolerability of esterified phytosterols have been clearly demonstrated (10).
Some studies have dealt with the interaction of genetics with the response of plasma lipid concentrations to changes in dietary fat or cholesterol (11,12). Individuals who carry the apolipoprotein (apo)E4/4 phenotype seem to have the highest response of plasma cholesterol to dietary cholesterol, whereas those with the apoE2/2 phenotype have the lowest (13–15). On the other hand, dietary sitostanol ester increases cholesterol synthesis rates and lowers LDL cholesterol (LDL-C) predominantly in individuals with the apoE4 genotype (16,17).
The mechanisms of control of cholesteryl ester transfer protein (CETP) require investigation because of the association of plasma CETP concentrations with the risk for premature atherosclerosis [for a review, see (18)]. CETP concentration in plasma is dependent on several factors, including environmental components, such as alcohol (19) and dietary cholesterol (20), and on genetic influences, such as the polymorphisms of CETP (21–25) and apoE (20). Furthermore, several studies have demonstrated that plasma CETP and cholesterol concentrations are interrelated; however, the mechanisms involved are not fully understood (26–30). In humans, plasma LDL-C and CETP concentrations decreased simultaneously with consumption of unsaturated fatty acid diets in one study (31), but not in another (32). In addition, the simultaneous variation of LDL-C concentration and of CETP by hypolipidemic drugs has been reported in some (26–30,33) but not all studies (29,34). On the other hand, cholesterol consumption by humans and rabbits simultaneously raises plasma concentrations of CETP and LDL-C, and CETP mRNA in rabbit liver and human adipose tissue (20,35), indicating that the CETP gene may be regulated by diet-induced changes in cholesterol. In one study on cholesterol consumption, the variation of plasma CETP, but not of LDL-C, was associated with the apoE gene polymorphism and was lowest in the apoE4/3 phenotype compared with the E3/2 and E3/3 phenotypes (20).
CETP polymorphisms have been related to variations in plasma HDL-C (22–25,36–38); some polymorphisms, i.e., Taq1B, I405V and R451Q, are associated with simultaneous variations in the concentrations of HDL and CETP (22–25,36,37). However, it is not known whether CETP gene polymorphisms are associated with variations in plasma lipoproteins other than HDL, although the Taq1B CETP polymorphism is related to the LDL size (24). Furthermore, in spite of reports of a close relationship between CETP plasma concentration and the intake of cholesterol, as well as fatty foods, in both humans and monkeys (20,27,31,32,35,39–41), no studies have reported an association of the CETP polymorphisms with the responses of the plasma CETP concentration to the intestinal absorption of cholesterol in food.
Our goals were to gain insight into the effect of the absorption of intestinal cholesterol on the concentrations of plasma lipids and CETP and to determine whether variations in these concentrations relate to common polymorphisms of CETP (I405V and Taq1B), as well as of apoE. This was accomplished by the dietary use of a PSE-enriched margarine, which is known to inhibit the intestinal absorption of cholesterol.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Sixty patients (50 women and 10 men) between 20 and 60 y of age, with body mass index < 30 kg/m2, were recruited from the outpatient clinics at the Clinical Hospitals of the University of São Paulo Medical School, São Paulo and Ribeirão Preto campuses. These were individuals with moderate primary hypercholesterolemia (mmol/L, mean ± SD: TC = 7.0 ± 0.8 and TG = 2.0 ± 0.8); only three participants had plasma TG > 3.4 mmol/L, i.e., 3.8, 3.9 and 4.8 mmol/L. The participants had not previously taken hypocholesterolemic drugs, and all secondary forms of hyperlipidemia were excluded. None of the women were using hormonal contraceptives. Subjects gave their informed written consent and the Ethics Committee of both hospitals involved approved the protocol.
Design.
The patients (n = 60) were enrolled in a double-blind, crossover study with random distribution into two groups of 30 patients each. Before joining the investigative protocol, they had all been consuming a prudent diet (baseline period) in which the energy distribution was protein (15%), carbohydrate (56%) and fat (28%), with a polyunsaturated/saturated fatty acid ratio close to 1.5 and a cholesterol intake of 170 mg/d. Thereafter, 30 participants were given margarine (20 g/d) without PSE (placebo) for 4 wk; they were next switched to margarine (20 g/d) with PSE (2.8 g/d = 1.68 g/d phytosterols) for the ensuing 4 wk. The other group (n = 30) began with consumption PSE and then switched to placebo. The phytosterols added contained 45% ß-sitosterol and 53% as a mixture of stigmasterol, campesterol and brassicasterol, esterified mainly with linoleic acid. Margarine was delivered in cups containing 20 g with the total daily amount eaten evenly distributed among the three major meals as an addition to slices of bread and equaling 8 g fat/d. A nutritionist carefully recorded the total amount eaten after weighing the returned cups once a week. Patients’ body weight did not change throughout the study. Three blood samples were drawn at the baseline period, that is, immediately before entering the experimental periods (placebo and PSE), and at wk 3 and 4 of each experimental period (placebo or PSE). Data represent the mean of three determinations for the baseline period and two determinations for each experimental period. The Van den Berg division of Gessy Lever, São Paulo, Brazil, supplied the margarines.
Plasma lipoprotein analysis.
After an overnight fast, venous blood samples were drawn into tubes containing 0.1% EDTA. The plasma was obtained by low speed centrifugation (1000 x g for 15 min) and the following preservatives were added per mL of plasma: aprotinin (0.1 trypsin inhibitor kU/L), 2 mmol/L benzamidine, 0.5% gentamicin plus 0.25% chloramphenicol, 0.5 mmol/L phenylmethylsulfonyl fluoride in dimethyl sulfoxide. All samples were stored at -70°C until further analysis and all determinations were conducted on the same batch.
ApoB-containing lipoproteins were precipitated with dextran sulfate/magnesium chloride (42) for the separation of HDL-C. Plasma cholesterol, TG and HDL-C were then measured with commercially available kits using the Cobas Mira (Roche) autoanalyzer system. Lipoprotein cholesterol fractions were estimated by the Friedewald formula (43). For the analyses of the responses of plasma lipids according to all polymorphisms, participants with plasma TG concentration > 2.8 mmol/L were excluded because type IIb hyperlipidemics might not be as responsive as type IIa subjects to plasma cholesterol–lowering drugs.
CETP concentration and lecithin-cholesterol acyltransferase (LCAT) activity.
CETP concentrations were measured using the ELISA procedure in the laboratory of Laurent Lagrost (INSERM U498, Dijon, France) (44). Plasma endogenous LCAT activity was determined according to the method of Dobiasova (45).
Determination of CETP and apoE polymorphisms.
DNA was extracted by the salting-out method from whole blood white cells as described by Miller et al. (46) and was analyzed for apoE (47) and for the I405V (23) and Taq1B CETP polymorphisms (19).
Statistical analysis.
Differences in plasma cholesterol, triacylglycerols, LDL-C, HDL-C, CETP concentrations and LCAT activity between placebo and PSE periods, as well as between the apoE phenotypes, were analyzed by the paired Student’s t test, whereas ANOVA was utilized to compare all values among the CETP genotypes. LDL-C reductions elicited by PSE according to the apoE3/3 and apoE3/4 polymorphisms were compared among three concentration ranges of LDL-C as measured during the baseline phase utilizing one-way ANOVA with Bonferroni’s multiple comparison post-test. The Spearman test was utilized to correlate the differences in CETP concentrations with those in total plasma cholesterol or LDL-C, represented by the PSE value minus the placebo value. Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Fasting plasma lipids, lipoproteins, CETP and LCAT values of all participants are presented during the baseline, placebo (PCB) and PSE-enriched margarine treatment periods (Table 1). Total plasma cholesterol and LDL-C concentrations diminished significantly after 4 wk of PSE consumption compared with the PCB and baseline periods. With PSE consumption, cholesterol and LDL-C concentrations were 10 and 12% lower, respectively, compared with the baseline period, and 6 and 8% lower, respectively, compared with the PCB period. TG and HDL-C concentrations did not differ. When all participants were divided into two groups according to their baseline plasma triacylglycerol levels, i.e., >2.3 mmol/L (68th percentile) and <1.9 mmol/L (51st percentile), they did not differ in total cholesterol (TC) and LDL-C responses to PSE treatment. Interestingly, compared with PCB, CETP concentrations decreased significantly from 2.98 ± 0.78 to 2.83 ± 0.63 mg/L after 4 wk of PSE consumption; however, LCAT plasma activity did not change.
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Polymorphisms, lipids and cholesterol.
Significant reductions of TC, LDL-C and CETP concentrations were observed in the E3/3 but not in the E3/4 phenotype. However, the percentage reduction did not differ between the phenotypes (Table 2). During the placebo phase, TC and LDL-C concentrations were lower in subjects with the VV phenotype than in those with the IV phenotype; however, with PSE consumption, these concentrations no longer differed among the genotypes (Table 3). In addition, the significant percentage reductions in TC and LDL-C depended on the presence of the I405V polymorphism because of their occurrence in the II and in the IV, but not in the VV genotype. Although the CETP concentration was lowered in the II genotype, plasma CETP was not influenced by the I405V polymorphisms because the percentage reduction did not differ among the three I405V genotypes.
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Negative correlations between plasma HDL-C concentration and LCAT activity were compatible with the physiologic roles played simultaneously by LCAT and CETP because LCAT makes HDL cholesteryl ester readily available for transfer to lighter density lipoproteins in exchange for TG, a process mediated by CETP. These findings also agreed with several studies that showed an inverse correlation between plasma CETP and HDL-C concentrations which, nonetheless, was not observed in the polymorphisms investigated here (20,23,25,39,48,49).
Correlations between plasma cholesterol and CETP concentrations indicated that mechanisms of regulation of plasma cholesterol and of CETP were dependent on common but as yet unknown mechanisms. We investigated whether and how variations of plasma cholesterol related to common apoE and CETP polymorphisms.
Previous studies utilizing different experimental approaches have shown that plant sterols (phytosterols) compete with cholesterol for intestinal absorption, thus reducing the cholesterol plasma concentration (1,4,50); this was attributed to an increased expression of the cell LDL receptor (51) or to a lower liver VLDL cholesterol synthesis rate (52). According to Vanhanen et al. (17) and Miettinen et al. (16), dietary sitostanol ester significantly lowered LDL-C in apoE4/4 subjects, but not in subjects with other apoE isoforms, a result attributed to greater absorption of dietary cholesterol in apoE4/4 subjects consuming their regular diets. These ideas were opposed by the recent work of Geelen et al. (53) showing that the LDL-C response to plant sterols was not related to the apoE polymorphism. Furthermore, the role of apoE in the regulation of dietary cholesterol absorption seems contradictory because of a lack of correlation between any apoE isoform and a rise in the LDL-C concentration after cholesterol consumption (20). This was observed in spite of the fact that the apoE phenotype distribution frequency in that work, as well as in our series, was close to that found in the literature (54). On the other hand, Martin et al. (20) indicated that the CETP concentration response to cholesterol feeding differed among the three apoE genotypes with a greater response in apoE3/2 than in E3/3 and apoE4/3 (E3/2: +37%, E3/3: + 18%, E4/3: + 9%). Contrary to others (16,17), and in agreement with Geelen et al. (53), we showed here that PSE lowered plasma TC and LDL-C concentrations, as well as CETP, independently of the apoE polymorphism. Whether and how a mutual influence occurs between the apoE and the CETP polymorphisms regarding efficiency in absorbing intestinal cholesterol is an open question that requires investigation in large population studies, a suggestion made by others (18).
The present work disclosed that during placebo consumption, plasma cholesterol and LDL-C were lower in the VV genotype, a novel finding not reported by others (18,48). Furthermore, dietary PSE was capable of lowering the TC and LDL-C concentrations in subjects with the II and IV, but not the VV genotype. On the other hand, CETP concentration was lowered by PSE in the II, but not in the IV and VV genotypes. Interestingly, compared with the VV genotype, subjects with the II and the IV genotypes had higher plasma cholesterol and LDL-C concentrations with placebo consumption and, coincidently, both were most responsive to PSE. Seemingly, the VV genotype, which had the lowest plasma cholesterol concentration, was the least responsive to PSE.
Contrary to the present report, other studies found a lower CETP concentration in VV compared with the II and IV genotypes (22,36). However, our data agreed with those from another study in that CETP concentrations were shown to be similar among the phenotypes of the I405V polymorphism (37). On the other hand, although others had reported higher CETP activity in the II (as well as in the B1B1) genotype, plasma LDL-C concentration was not reported (23). Therefore, our work disclosed for the first time that plasma TC and LDL-C concentrations were dependent on the I405V CETP genotypes, but that the concentrations of CETP were independent of both the I405V and the Taq1B CETP polymorphisms during either placebo or PSE consumption in spite of a general effect of PSE of lowering plasma CETP concentrations.
Interestingly, with PSE consumption, correlations between plasma CETP and total cholesterol observed during placebo were maintained, whereas those between CETP and LDL-C disappeared. In addition, TC and LDL-C concentrations with placebo consumption were lower in subjects with the VV phenotype than in those with the II and IV phenotypes; however, these differences were no longer present with PSE consumption. This likely occurred because the effect of the I405V CETP polymorphism on the regulation of plasma cholesterol was blunted once a peak plasma cholesterol was attained. The biochemical mechanisms behind this process require investigation and may be critical for the regulation of plasma cholesterol in populations consuming diets that raise the plasma cholesterol concentration.
In summary, this study demonstrated that PSE brought about a reduction in plasma cholesterol and LDL-C concentrations presumably via an impairment of intestinal cholesterol absorption (5,50). This pattern of response of plasma lipids is related to the I405V CETP polymorphism in which the percentage reductions in TC with consumption of PSE for the II, IV and VV phenotypes were 7.2, 4.2 and not significant, respectively, whereas LDL-C significant reductions occurred only for II (9.5%). However, the CETP concentration diminished only in the II phenotype.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 A.M. Lottenberg and V. S. Nunes contributed equally to this work.
4 Abbreviations used: apo, apolipoprotein; CETP, cholesteryl ester transfer protein; HDL-C, HDL cholesterol; LCAT, lecithin-cholesterol acyltransferase; LDL-C, LDL cholesterol; PSE, plant sterol ester; TC, total cholesterol; TG, triacylglycerols.
Manuscript received 2 December 2002. Initial review completed 2 January 2003. Revision accepted 7 March 2003.
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LITERATURE CITED |
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