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Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Human Plasma Levels of Vitamin E and Carotenoids Are Associated with Genetic Polymorphisms in Genes Involved in Lipid Metabolism^1–3,

⁴ INSERM, U476 "Nutrition Humaine et Lipides", INRA, UMR1260, and Univ Méditerranée Aix-Marseille 2, Faculté de Médecine, IPHM-IFR 125, Marseille, F-13385 France; and ⁵ INRA, UMR1019 "Nutrition Humaine", Saint-Genes-Champanelle, F-63122 France

^* To whom correspondence should be addressed. E-mail: patrick.borel{at}medecine.univ-mrs.fr.

	ABSTRACT

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
Vitamin E and carotenoids are fat-soluble micronutrients carried by plasma lipoproteins. Their plasma concentrations are governed by several factors, some of which are genetic, but data on these genetic factors remain scarce. We hypothesized that genes involved in lipid metabolism, i.e. the genes implicated in intestinal uptake, intracellular trafficking, and the lipoprotein distribution of lipids, play a role in the plasma concentrations of these micronutrients. To verify this hypothesis, we assessed whether the plasma status of vitamin E and carotenoids is related to genes involved in lipid metabolism. Fasting plasma vitamin E (- and -tocopherol) and carotenoid (- and ß-carotene, lutein, lycopene, ß-cryptoxanthin, and zeaxanthin) concentrations were measured in 48 males and 80 females. The following genes were genotyped [single nucleotide polymorphisms (SNP)]: apolipoprotein (apo) A-IV, apo B, apo E, lipoprotein lipase, and scavenger-receptor class B type I (SR-BI). Plasma -tocopherol concentrations were different (P < 0.05) in subjects bearing different SNP in apo A-IV, apo E, and SR-BI. Plasma -tocopherol concentrations were different (P < 0.05) in subjects bearing different SNP in apo A-IV and SR-BI. -Carotene concentrations were different (P < 0.05) in subjects bearing different SNP in SR-BI. ß-Carotene concentrations were different (P < 0.05) in subjects bearing different SNP in apo B and SR-BI. Lycopene concentrations were different (P < 0.05) in subjects bearing different SNP in apo A-IV and apo B. ß-Cryptoxanthin concentrations were different (P < 0.05) in subjects bearing different SNP in SR-BI. Plasma lutein and zeaxanthin concentrations did not differ in subjects bearing different SNP. Most of the differences remained significant after the plasma micronutrients were adjusted for plasma triglycerides and cholesterol. These results suggest that genes involved in lipid metabolism influence the plasma concentrations of these fat-soluble micronutrients.

	Introduction

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

The uptake of vitamin E and carotenoids by the intestinal cell is poorly understood. It has long been assumed that these fat-soluble molecules are absorbed by a passive diffusion mechanism. However, recent results from our laboratory (5–7) and 2 other teams (8,9) have established that the scavenger receptor class B type I (SR-BI)⁸ is involved in the intestinal uptake of these micronutrients. Furthermore, other intestinal membrane transporters, such as Niemann-Pick C1-like 1 (10) and cluster determinant 36 (8), may also be involved in this phenomenon. After uptake by enterocytes, these fat-soluble molecules are incorporated into chylomicrons and then secreted into the lymph. The microsomal triglyceride transfer protein, which is involved in chylomicron packaging, is involved in the incorporation of vitamin E into these lipoproteins (11), but its role in carotenoid metabolism has not yet been studied. Finally, the protein(s) involved in intracellular transport of fat-soluble micronutrients in the aqueous environment of the enterocyte have not been identified, although the cytosolic fatty acid-binding proteins (FABP; intestinal-FABP and liver-FABP) may well be candidates.

It is assumed that following absorption, vitamin E and carotenoids are distributed to body tissues through plasma lipoproteins. Indeed, vitamin E and carotenoids are found only in lipoproteins (VLDL, LDL, and HDL), although in different proportions (12,13). This difference in distribution in lipoprotein classes has not been fully explained and probably depends on several factors, including micronutrient hydrophobicity (14) and micronutrient transfer rates between lipoprotein classes and from lipoproteins to tissues (15–17). Given that the plasma vehicle of vitamin E and carotenoids is lipoproteins, it is reasonable to hypothesize that the plasma status of these micronutrients is governed by proteins involved in lipoprotein metabolism, i.e. apolipoproteins (apo B, apo E, apo A-IV, apo C-III, etc.), lipoprotein lipase (LPL), hepatic lipase, phospholipid transfer protein, cholesteryl ester transfer protein, and lecithin cholesterol acyltransferase. This hypothesis is essentially supported by 2 observations. First, the exchange of vitamin E between lipoproteins (15,16) is mediated by phospholipid transfer protein (18,19) and it has been suggested that cholesteryl ester transfer protein and/or lecithin cholesterol acyltransferase is involved in xanthophyll transfer between lipoproteins (17). Second, SR-BI is involved in the transfer of -tocopherol from HDL to tissues (20) and, as stated above, this transporter is also involved in intestinal cell uptake of carotenoids and vitamin E. Hence, there is a reasonable rationale to suppose that this membrane transporter also plays a role in determining the plasma concentration of these micronutrients.

To summarize, the observations presented above strongly suggest that proteins involved in lipid metabolism are also involved in the absorption, intracellular trafficking, and plasma transport of vitamin E and carotenoids. Because several single nucleotide polymorphisms (SNP) in genes coding for these proteins have been related to lipid status in humans (21–24), we designed this study to assess whether SNP in these genes correlate with plasma concentrations of vitamin E and carotenoids. Such associations would suggest a direct or indirect role of these genes on the metabolism of these micronutrients. We studied SNP in 5 genes involved in lipid absorption and lipoprotein metabolism. The 1st gene studied encodes a membrane protein involved in the uptake/efflux of lipids, vitamin E, and carotenoids through cell membranes (SR-BI). The 2nd gene encodes an apoprotein secreted by the intestine and associated with chylomicrons (apo A-IV). The 3rd gene encodes an apoprotein involved in hepatic VLDL secretion and LDL clearance (apo B). The 4th gene encodes an apoprotein involved in triglyceride-rich lipoprotein remnant clearance (apo E), and the 5th gene encodes a lipase responsible for the lipolysis of lipoprotein triglycerides (LPL).

	Subjects and Methods

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
    Subjects. Results of this observational study were obtained from baseline values of Caucasian subjects enrolled in the Medi-RIVAGE study (25,26). Subjects (18–70 y old) were recruited at the Center for Detection and Prevention of Arteriosclerosis at La Timone University Hospital (Marseille, France). The Medi-RIVAGE protocol was approved by the regional ethics committee in Marseille. Given that the Medi-RIVAGE study enrolled subjects displaying moderate risk for cardiovascular disease, the subjects presented at least 1 of the following criteria: fasting plasma cholesterol, 6.5–7.7 mmol/L; plasma triacylglycerols, 2.1–4.6 mmol/L; plasma glycemia, 6.1–6.9 mmol/L; systolic and diastolic blood pressure between 140–180 and 90–105 mm Hg, respectively; BMI > 27 kg·m^–2; smoking; sedentary lifestyle; family history of cardiovascular disease. An upper limit was fixed for lipid variables, glycemia, and blood pressure to exclude subjects who were taking drug therapy for these conditions. Eligible volunteers signed informed consent forms as required by the institution's ethic committee (ethic committee number 98/25). Subject characteristics and nutrient intakes are given in Table 1.

Apo A-IV (22), apo B (23), and LPL (27) were genotyped via PCR amplification followed by enzymatic digestion (restriction isotyping) and restriction fragment lengths were visualized by PAGE (details on SNP, primers, and restriction enzymes are given in Supplemental Table 1).

The Cys112Arg and Arg158Cys variants in the apo E gene were simultaneously assayed according to the Hixson and Vernier's method and Hha I digestion (28).

The 3 SCARB-1 (gene that encodes SR-BI) polymorphisms were carried out by allelic discrimination using the 5' nuclease assay with specific fluorogenic probes as described in the original method (29). Real-time PCR was monitored on a Stratagene Mx4000 apparatus.

    Vitamin E extraction and HPLC analysis. Both - and -tocopherol were extracted from 250-µL aqueous samples using the following method. To begin, 200 µL of distillated water was added to 50 µL plasma. Tocol, which was used as internal standard, was added to the samples in 250 µL ethanol. The mixture was extracted once with 1 volume of hexane. The hexane phase obtained after centrifugation (500 x g; 10 min, 4°C) was evaporated to dryness under nitrogen and the dried extract was dissolved in 200 µL methanol. A volume of 2 µL was used for HPLC analysis. -Tocopherol, -tocopherol, and tocol were separated using a 250- x 4.6-nm reverse-phase C₁₈, 5-µm Zorbax column (Interchim) and a guard column. The mobile phase was 100% methanol. Flow rate was 1.5 mL/min and the column was kept at a constant temperature (30°C). The HPLC system comprised a Dionex separation module (P680 HPLC pump and ASI-100 Automated Sample Injector) and a Jasco fluorimetric detector. Tocopherols were detected at 325 nm after light excitation at 292 nm and were identified by retention time compared with pure (> 97%) standards purchased from Fluka. Quantification was performed using Chromeleon software (version 6.50 SP4 Build 1000) comparing peak area with standard reference curves.

    Carotenoid extraction and HPLC analysis. Carotenoids were extracted and analyzed as previously described (30). Briefly, 200 µL of plasma was deproteinized by adding 1 volume of ethanol containing the carotenoid echinenone (as internal standard). Carotenoids were extracted twice by the addition of 2 volumes of hexane. The hexane phases obtained after centrifugation (500 x g; 10 min, 4°C) were pooled and evaporated completely under nitrogen. The dried extract was dissolved in 200 µL of dichloromethane:methanol mixture (65:35; v:v). All extractions were performed at room temperature under yellow light to minimize light-induced damage. A volume of 80 µL was used for HPLC analysis. The HPLC system consisted of a 150- x 4.6-mm, RP C₁₈, 3-µm Nucleosil column (Interchim) coupled with a 250- x 4.6-mm C₁₈, 5-µm Hypersil guard column. The mobile phase consisted in acetonitrile/methanol containing 50 mmol/L ammonium acetate:water:dichloromethane (70:15:5:10; v:v:v:v). The flow rate was 2 mL/min. The columns were kept at a constant temperature (30°C). The HPLC system consisted of a Water system equipped with a UV-visible photodiode-array detector (Waters 996). Carotenoids were detected at 450 nm and identified by retention time compared with pure (>95%) standards, which were generously donated by Dutch State Mines. Quantifications were performed using Millennium 32 software (version 3.05.01) comparing peak area with standard reference curves.

    Statistics. Values cited in the text are means ± SD. All statistical tests were performed using the SAS software package. Histograms with corresponding Gaussian curves were analyzed to test whether the distribution of the dependent variables was normal. When the distribution was too far from normal, the variable was converted into logarithm 10.

Subject characteristics and nutrient intake differences between men and women were assessed using a Student's t test.

Before testing the effect of genotypes on the dependent variables, interfering covariables (adjustment factors) were identified by 2 approaches. In the first approach, each dependent variable was tested in univariate general linear models with the following independent qualitative variables: physical activity (3 ranges), antihypertensive treatment, tobacco (3 formats: never a smoker, currently a smoker, a former smoker), and menopausal status. In the other approach, linear Pearson correlations between the dependent variables and the quantitative covariables, BMI and alcohol intake, were calculated; any that were significant at P < 0.05 were retained. Covariables identified by either of the 2 methods were included as adjustment factors for testing the genotype effect. Age was always included in the adjustment.

The effects of the genotypes on the dependent variables (i.e. plasma vitamin E and carotenoids) were tested systematically for the whole subject population and for men and women separately using univariate general linear models. Results include adjusted P-values, nonadjusted means, and SD. Where the effects of the genotypes differed according to gender, results are given separately for men and women.

	Results

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
    Subject characteristics and nutrient intakes. Forty-eight men and 80 women were enrolled in the study (Table 1). The vitamin E intake of the subjects was close to the recommended dietary allowances [12 mg/d for a young adult (31)], but women had a significantly lower vitamin E intake than men. Intake of - and ß-carotene, which did not differ between men and women, was 4 mg/d. This was lower than the intake observed in previous studies of French adults (6–7 mg/d) (32,33).

    Fasting plasma vitamin E and carotenoid concentrations and effect of gender. Men had higher -tocopherol concentrations than women (Table 2). Conversely, women had higher plasma -carotene, ß-carotene, and ß-cryptoxanthin concentrations than men.

    Effect of SR-BI SNP on plasma levels of -carotene.

    Effect of apo B and apo-IV SNP on plasma levels of lycopene. Two genes were related to plasma lycopene: apo B and apo A-IV (Table 5). Subjects bearing the C allele at apo B -516 had significantly lower plasma lycopene concentrations than subjects homozygous for the T allele. Women bearing the A allele at apo A-IV-Ser-347 had higher plasma lycopene than women bearing the TT genotype.

    Effects of SR-BI SNP on plasma levels of ß-cryptoxanthin. Two SNP in SR-BI were related to ß-cryptoxanthin plasma concentrations (Table 5). ß-Cryptoxanthin concentration was 40% higher in male carriers of allele A in SR-BI exon 1 than in male carriers of the GG genotype. Women bearing a T allele at SR-BI exon 8 had 28% lower plasma ß-cryptoxanthin concentrations than the CC carriers at this SNP.

    Relationships between SNP and plasma micronutrient levels after adjustment for cholesterol and triglycerides. The fact that positive bivariate correlations were found between plasma total cholesterol and both -tocopherol (r = 0.484; P < 0.001) and -tocopherol (r = 0.186; P = 0.038) prompted us to test the relationships between these 2 vitamin E forms and the studied polymorphisms with and without adjustment for plasma cholesterol level. Furthermore, because a positive bivariate correlation was also found between plasma triglycerides and -tocopherol (r = 0.197; P = 0.030), -tocopherol was thus adjusted for both cholesterol and triglyceride levels.

After adjustment, the effect of the apo A-IV polymorphism on -tocopherol levels (shown in Table 4) was no longer significant. The effect of apo E polymorphisms on -tocopherol remained significant for men and became nearly significant for the whole population (P = 0.057). The effect of the SR-BI exon 8 polymorphism on -tocopherol in men remained significant. Finally, the adjustments did not notably modify the results of the associations between gene polymorphisms and -tocopherol levels.

There were negative bivariate correlations between plasma triglycerides and -carotene (r = –0.249; P = 0.005), ß-carotene (r = –0.226; P = 0.011), and ß-cryptoxanthin (r = –0.249; P = 0.005). The relationships between these carotenoids and the various gene polymorphisms were thus tested with and without adjustment for triglycerides. The adjustments did not noticeably modify the results of the associations observed between polymorphisms and -carotene and ß-carotene levels (Table 5). In the case of ß-cryptoxanthin, the adjustment did not noticeably modify the association with SR-BI exon 1 polymorphism but turned the association with SR-BI exon 8 (P = 0.084) into a tendency.

On the whole, these adjustments did not markedly modify the preadjustment associations observed.

	Discussion

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 
Because vitamin E and carotenoids are fat soluble and follow the fate of lipids in the body, our hypothesis was that proteins (and thus encoding genes) that govern the metabolism of lipids can either directly or indirectly affect the absorption and plasma transport of these micronutrients and, thus, their plasma concentrations. The selection of candidate genes was based on their well-known key roles in lipid transport (SR-BI) and lipoprotein metabolism (apo A-IV, B, E, and LPL). The choice of candidate SNP was based on studies showing that these SNP have a phenotypic effect on lipid metabolism. Before the relationships observed in this study can be discussed in detail, it should be emphasized that the lack of relationship between a given SNP and the plasma concentration of a micronutrient does not mean that the gene carrying this SNP cannot be involved in the metabolism of that micronutrient. Indeed, obviously no study has enough statistical power to identify all the potential relationships and it is possible that the selected SNP was not an appropriate marker of the candidate gene. Conversely, when a significant relationship is observed between a given SNP and the plasma concentration of a micronutrient, this suggests that the gene carrying this SNP is involved in this plasma concentration in the sample population studied. However, despite being significant, a relationship is not definitive evidence and would require confirmation in other populations.

Several SNP in SCARB-1 (the gene coding for SR-BI) were related to plasma concentrations of - and -tocopherol, - and ß-carotene, and ß-cryptoxanthin. This is not surprising, because the SR-BI membrane transporter is involved in the intestinal uptake of vitamin E and carotenoids (5–9) as well as tissue uptake of HDL vitamin E (20,34). It is therefore implicated in the flux of these micronutrients into and from the plasma. Results obtained by Mardones et al. (34) on vitamin E metabolism in (SR-BI)-deficient mice support this hypothesis.

Because vitamin E and carotenoids are carried exclusively by plasma lipoproteins, the relationships between SNP in apolipoproteins and the plasma levels of these micronutrients were not surprising. Furthermore, the relationship between apo E variants and plasma concentration of -tocopherol confirm previous findings (35,36). Indeed, as observed by Gomez-Coronado et al. (35), we found that subjects bearing the E2 allele had lower -tocopherol concentrations than those bearing the more common E3 allele. With the exception of the 4 E4-homozygous subjects, the subjects bearing the E4 allele had the higher -tocopherol concentrations. These results were nevertheless different from those observed by Ortega et al. (36) in Spanish children. Indeed, in contrast to Ortega's team, we did not find any association between plasma lycopene or -carotene and apo E variants. There was another apolipoprotein polymorphism that was related to plasma -tocopherol: apo A-IV (although this association disappeared after adjustment for cholesterol). Apo A-IV, which is secreted as a chylomicron and intestinal VLDL apoprotein, was also related to both plasma -tocopherol and plasma lycopene. It should be noted that only carotenes (ß-carotene and lycopene) were related to the apo B polymorphism. This is not surprising, because this apoprotein is only found in triglyceride-rich lipoproteins (VLDL and LDL) and because these 2 carotenoids are mainly recovered in these lipoparticles, whereas the xanthophylls (lutein, zeaxanthin, and ß-cryptoxanthin) and vitamin E are more equally distributed between apo B and non-apo B lipoproteins (12,13). Furthermore, vitamin E and the xanthophylls readily exchange between apo B lipoproteins and HDL (15–17), whereas the carotenes, if they do exchange, do so at a lower rate (17), thus making their association with apo B stronger.

The lack of relationship between the LPL SNP and plasma status of the studied micronutrients suggests that this intravascular lipolytic enzyme has no major effect on the fasting plasma concentrations of these micronutrients. However, a potential role of this enzyme in the plasma metabolism of these micronutrients in the postprandial period could not be determined with the experimental design used.

In conclusion, this study identified several genes potentially involved in the plasma status of vitamin E and carotenoids. SCARB-1, the gene coding for SR-BI, seems to play a ubiquitous role, because it was related to the plasma status of several studied micronutrients. Certain apolipoprotein genes also appear to be involved in the plasma status of these micronutrients. The study also confirmed the previously described association between apo E variants and plasma -tocopherol and we found that 2 other apolipoproteins, apo A-IV and apo B, were associated with the plasma status of vitamin E and carotenoids.

	FOOTNOTES

 
¹ This study was supported by the French Ministry of Research (an AQS grant plus S. Vincent-Baudry's salary), the INSERM (an IDS grant), the Provence-Alpes-Côte d'Azur Regional Council, the Bouches du Rhône General Council, CRITT-PACA, and the following companies: Rivoire & Carret Lustucru, Jean Martin, Le Cabanon, Boulangerie Coagulation Surgelés, Distplack Mariani, and Minoterie Giraud.

² Author disclosures: P. Borel, M. Moussa, E. Reboul, B. Lyan, C. Defoort, S. Vincent-Baudry, M. Maillot, M. Gastaldi, M. Darmon, H. Portugal, R. Planells and D. Lairon, no conflicts of interest.

³ Supplemental Table 1 is available with the online posting of this paper at jn.nutrition.org.

⁸ Abbreviations used: apo, apolipoprotein; FABP, fatty acid-binding protein; LPL, lipoprotein lipase; SNP, single nucleotide polymorphism; SR-BI, scavenger-receptor class B type I.

Manuscript received 18 July 2007. Initial review completed 21 August 2007. Revision accepted 17 September 2007.

	LITERATURE CITED

TOP ABSTRACT Introduction Subjects and Methods Results Discussion LITERATURE CITED

 

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