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Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Hypo- and Hyperresponse to Egg Cholesterol Predicts Plasma Lutein and ß-Carotene Concentrations in Men and Women^1,2

Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269-4017

³ To whom correspondence should be addressed. Email: richard.m.clark{at}uconn.edu.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The purpose of this study was to determine whether the plasma response to dietary cholesterol from eggs is associated with the plasma carotenoid response and whether gender influences the carotenoid response. Using a crossover design, 40 subjects classified as either hyper- (10 men and 10 women) or hyporesponders (10 men and 10 women) to dietary cholesterol consumed an egg (EGG, 640 mg/d additional dietary cholesterol and 600 µg lutein + zeaxanthin) or placebo (SUB, 0 mg/d cholesterol, 0 µg lutein + zeaxanthin and 568 µg ß-carotene) diet for 30 d, followed by a 3-wk washout period and the alternate diet. Plasma concentrations of lutein and ß-carotene after each dietary period were then examined to determine whether the response to carotenoid intake was similar to that seen for dietary cholesterol. After the EGG period, the increase in plasma lutein in female hyperresponders (mean increase ± SD; 0.32 ± 0.19 µmol/L) and male hyperresponders (0.26 ± 0.11 µmol/L) was significantly greater than that of their hyporesponsive counterparts (0.16 ± 0.18 µmol/L for women and 0.14 ± 0.11 µmol/L men). Gender was not a significant factor influencing lutein response. Both men and women classified as hyperresponders significantly increased plasma ß-carotene after the SUB period, whereas their hyporesponsive counterparts were not affected. The increase in plasma ß-carotene in female hyperresponders (0.29 ± 0.48 µmol/L) was significantly greater than that in male hyperresponders (0.07 ± 0.07 µmol/L). We conclude that plasma responses to cholesterol and carotenoids are related and that gender influences the ß-carotene response to a greater degree than the lutein response.

KEY WORDS: • carotenoid • lutein • ß-carotene • cholesterol • eggs

The potential protective effect of lutein and its isomer zeaxanthin against age-related macular degeneration (1–5) and cataracts (6–8) has stimulated interest in eggs as a dietary source of these carotenoids. Although eggs contain less lutein than spinach and other plant foods, the matrix of the yolk was shown to enhance the bioavailability of carotenoids (9,10). Other factors such as overall diet quality or physiologic differences between individuals can further influence carotenoid bioavailability (11–13). The purpose of this study was to investigate factors intrinsic to the individual that may influence carotenoid utilization.

In this study, the plasma responses to cholesterol, lutein (provided by eggs), and ß-carotene (provided by an egg substitute) were compared within the same subject. A great deal of individual variation in the plasma response to dietary cholesterol and carotenoids has been reported in the literature. Some individuals do not respond or respond only slightly to dietary cholesterol (14–16) or carotenoids (11), whereas others display large plasma responses. This has led to the concept of classifying individuals as hyper- or hyporesponders to dietary cholesterol and carotenoids.

Cholesterol and carotenoids are dietary lipids that share many common steps during absorption, transport in the blood, and tissue storage (11–13). Recent experiments showed that membrane transporters associated with cellular uptake and efflux cholesterol may also transport carotenoids. In Drosophila, a scavenger receptor, similar to the scavenger receptor class B type (SR-BI)⁴ and CD36 receptors in mammals, mediates cellular uptake of carotenoids (17). Reports utilizing SR-BI knockout mice (18) and Caco-2 cells (19) identified SR-BI as a common mediator for both cholesterol and ß-carotene absorption. Another study suggested that lutein uptake by Caco-2 cells is due in part to the SR-BI receptor (20). Although the response to changes in dietary cholesterol and carotenoids varies greatly among individuals, the identification of common transporters strengthens the potential for shared regulation of cholesterol and carotenoids within an individual.

Gender may also be a factor that affects the utilization of carotenoids. Studies from several countries have reported that plasma levels of most carotenoids are higher in women than in men. This is especially true for ß-carotene, -carotene and, ß-cryptoxanthin the major provitamin A carotenoids in the plasma (21–25). Variation in overall diet quality may contribute to the influence of gender; however, differences in physiology must also be considered (26).

This study had 3 objectives. The first was to determine whether the plasma response to dietary cholesterol is related to the plasma response to carotenoids. The second objective was to determine whether the plasma response to carotenoids is influenced by gender, and the third was to determine whether individuals respond similarly to lutein and ß-carotene.

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
    Materials. Liquid-pasteurized whole eggs and cholesterol-free/fat-free eggs (placebo) were purchased from Better Brands. ß-Carotene and -carotene were obtained from Sigma Chemical. Ethyl-ß-apo-8'-carotenoate was obtained from Fluka.

    Subjects. Plasma samples from subjects who had fasted for 12 h were collected in the morning (0600–0900) from 20 men and 20 premenopausal women and used in this study. Subjects were selected from a larger study with 40 men and 51 premenopausal women based on plasma cholesterol responses to egg consumption (27,28). The current study compared 10 men and 10 women exhibiting the greatest plasma cholesterol response (hyperresponders) with 10 men and 10 women with the lowest response to egg consumption (hyporesponders). The 20 subjects classified as hyperresponders in this study had increased plasma cholesterol 0.10 mmol/L for each 100 mg of egg cholesterol consumed/d, whereas the 20 hyporesponders experienced an increase <0.04 mmol/L for each 100 mg of cholesterol consumed/d.

    Diet and study design. The experimental protocol was approved by the University of Connecticut's Institutional Review Board, and written informed consent was obtained from each subject. The study utilized a randomized crossover design, with subjects initially assigned to an egg (EGG) or placebo (SUB) group for 30 d, followed by a 3-wk washout period, after which the 2nd dietary period began. Subjects assigned to the EGG group consumed commercially packaged whole eggs, which contributed 640 mg of cholesterol and 600 µg of lutein + zeaxanthin to the diet each day. In contrast, those receiving the SUB consumed an egg substitute that contained no lutein + zeaxanthin or cholesterol but did contain 568 µg/d ß-carotene. The 2 products were identical in terms of color and consistency. Daily amounts were provided in individual containers, and subjects were asked to return any uneaten product at the end of the week. The study participants were given free choice concerning how they incorporated the eggs/egg substitutes into their daily diet. Participants were expected to adhere to the National Cholesterol Education Program (NCEP) Step I diet for the duration of the study, and detailed dietary instructions were provided. To ensure compliance, subjects completed seven 24-h dietary records during each treatment period, both of which included 2 weekend days. Dietary analysis was performed using Nutritional Data System for Research software version 4.0, developed by the Nutrition Coordinated Center, University of Minnesota, Minneapolis, MN. This database also allows lutein + zeaxanthin, -carotene, and ß-carotene consumption to be determined.

    Plasma lipid analysis. Plasma cholesterol and triglyceride (TG) were determined enzymatically with commercial kits from Roche-Diagnostics (29,30). HDL cholesterol (HDL-C) was measured in the supernatant after precipitation of apolipoprotein (apo) B-containing lipoproteins, (31) and LDL cholesterol (LDL-C) was determined using the Friedewald equation (32).

    Carotenoid analysis. To determine the carotenoid content of the egg and egg substitute, a 100-µL aliquot was placed in a screw-top test tube with 1 mL pyrogallol in reagent alcohol and 5 mL 15% KOH in methanol. The samples were saponified at 60°C in a water bath for 1 h. After the tubes were allowed to cool, water was added. The sample was then extracted 3 times with hexane. The hexane layer was separated and transferred to another tube. The hexane was removed from the extracted lipid sample with a stream of nitrogen. An internal standard (ethyl-ß-apo-8'-carotenoate) was added to the sample and reconstituted with 2-propanol for injection into the HPLC.

Plasma samples were prepared for HPLC analysis as previously described with minor changes (23). Briefly, 200 µL of plasma was mixed with an equal volume of absolute ethanol containing BHT and ethyl-ß-apo-8'-carotenoate (internal standard). The sample was then extracted 3 times with hexane containing BHT. Samples were centrifuged to facilitate phase separation (1,000 x g; 2.0 x min). The hexane layers were combined and the solvent removed with a stream of nitrogen. The residuals were reconstituted with 100 µL of 2-propanol and placed in HPLC injection vials.

Carotenoids were analyzed using a Waters HPLC system. A Varian HPLC column (100 x 4.6-mm microsorb-MN 100-3 C-18) preceded by an Upchurch C-18 guard column (Upchurch Scientific) with an isocratic mobile phase consisting of 80% acetonitrile:15% dioxane:2.5% methanol:2.5% 2-propanol:0.01% triethylamine:0.01% ammonium acetate. Detection of internal standard and carotenoids was at 450 nm. All solvents used were of HPLC grade and were filtered and degassed before use. Standard curves were compiled from HPLC-purified lutein, zeaxanthin, and commercially purchased -carotene and ß-carotene.

    Statistical analysis. A 3-way repeated measures ANOVA was used. The main effects were dietary treatment, gender, and response classification based on plasma cholesterol. A paired t test was used to evaluate differences in plasma carotenoids within individuals. The results presented in the text are means ± SD. Differences were considered significant at P < 0.05.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The analysis of the 7-d dietary records confirmed that all subjects complied with the requirements of the National Cholesterol Education Program step I diet. A significantly greater intake of dietary cholesterol was reported when the EGG, compared with the SUB diet, was consumed (764.3 ± 67.1 and 166.9 ± 118.3 mg/d, respectively). In addition, the contribution of energy derived from total (31.4 ± 5.5%) and saturated fat (10.9 ± 2.4%) during the EGG period was significantly higher than the total (26.6 ± 7.1%) and saturated fat (9.4 ± 2.6%) consumed during the placebo period.

    Characteristics of the study population. The age or anthropometric characteristics of the women in this study did not differ. Women classified as hyperresponders were 33.0 ± 8.4 y old with a BMI of 23.8 ± 3.5 kg/m². The women hyporesponders were 31.7 ± 9.5 y old and had a BMI of 21.8 ± 3.0 kg/m². The men classified as hyperresponders were older (39.5 ± 11.5 y) than the male hyporesponders (27.0 ± 6.2 y) but their BMI did not differ (hyperresponders 24.5 ± 3.1 kg/m²; hyporesponders 26.2 ± 6.0 kg/m²).

    The effect of diet, gender, and response on plasma lipid concentrations. The subjects in this study were selected on the basis of their plasma response to dietary cholesterol. Both male and female hyperresponders had significantly higher total cholesterol (TC) and LDL-C after EGG intake (Table 1). Men and women did not differ in TC or LDL-C. As can be expected, women had higher (P < 0.001) HDL-C concentrations than men, with the greatest elevation (P < 0.001) occurring in hyperresponders after EGG intake. Male hyperresponders also had increased HDL-C (P < 0.001) after EGG intake. Men had significantly higher TG than women.

All 20 subjects classified as hyperresponders had an increase in plasma lutein during the EGG period compared with SUB (Figs. 1 and 2); 15 of the hyporesponders also had an increase in plasma lutein, although to a lesser degree than hyperresponders. The remaining 5 hyporesponders had little or no increase in plasma lutein. Plasma lutein increased by 0.32 µmol/L in the female hyperresponders; the increase in the male hyperresponders was 0.26 µmol/L. The female hyporesponders had an increase of 0.16 µmol/L and the change in the male hyporesponders was 0.14 µmol/L. Therefore, hyporesponders exhibited only half the increase that occurred in their hyperresponder counterparts.

View larger version (23K): [in this window] [in a new window]   FIGURE 1  Plasma lutein concentrations in 40 male and female hypo- and hyperresponders to egg cholesterol before and after 30 d of consuming eggs contributing 600 µg/d lutein and zeaxanthin. The baseline plasma lutein concentration is after the SUB period with no lutein added to the diet.

View larger version (23K): [in this window] [in a new window]   FIGURE 2  Plasma ß-carotene concentrations in 40 male and female hypo- and hyperresponders to egg cholesterol before and after 30 d of consuming eggs contributing 568 µg/d lutein and zeaxanthin. The baseline plasma ß-carotene concentration is after the EGG period when no ß-carotene was added to the diet.

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Numerous studies report a large heterogeneity in the plasma response to dietary cholesterol (14–16) and dietary carotenoids (11). This led to the classification of individuals as hyper- or hyporesponsive to these dietary components. It has been estimated that 15–25% of the general population is hyperresponsive to dietary cholesterol (14). Plasma responses to dietary carotenoids have not been studied extensively and reports of hyper- and hyporesponse to an individual carotenoid, usually ß-carotene, may not predict responses to other carotenoids (5,33–40). In addition, the amount of carotenoid consumed may influence the response classification because consumption of pharmacologic doses of ß-carotene eliminates the bimodal ß-carotene plasma response (41).

In the present study, both men and women classified as hyperresponders to egg cholesterol had higher baseline plasma concentrations of lutein, zeaxanthin, -carotene, and ß-carotene. Hyperresponders also had significantly greater increases in plasma lutein after the EGG period and ß-carotene after the SUB period compared with the hyporesponders. This supports the existence of a relation between the plasma response to dietary cholesterol and carotenoids. However, some individuals who were hyperresponsive to lutein were not hyperresponsive to ß-carotene. Most individuals had increased plasma lutein after the EGG period, but a large number of individuals did not respond to ß-carotene. A recent study comparing plasma lutein and ß-carotene after the consumption of lutein-containing yellow carrots, reported an increase in plasma lutein, but no increase in ß-carotene (40). A study by Johnson et al. (5) found that feeding spinach and corn led to a significant increase in plasma lutein, but not ß-carotene. The authors concluded that hyperresponders to lutein may not experience the same response to ß-carotene. This conclusion was generally true in our study.

In contrast to the lack of consistent associations within hyperresponders, a hyporesponse to cholesterol was associated with an attenuated plasma response to dietary lutein and ß-carotene. All of the men classified as hyporesponders to cholesterol were nonresponders to ß-carotene and hyporesponders to lutein. Female hyporesponders did not significantly increase ß-carotene after the SUB period and generally exhibited the smallest increases in plasma lutein concentrations after the EGG period. There are several steps during absorption and transport that are shared by cholesterol, lutein, and ß-carotene; these may positively or negatively influence their plasma concentrations. In addition to these shared steps, ß-carotene may be converted to vitamin A during absorption. If cholesterol, lutein, and ß-carotene plasma responses are reduced because of a common alteration, this could mask variation due to ß-carotene cleavage. Alternatively, when shared factors facilitate cholesterol, lutein, and ß-carotene absorption, efficient cleavage of ß-carotene would reduce plasma levels of ß-carotene but not cholesterol and lutein. Differences in intestinal cleavage of ß-carotene may explain the lack of a consistent association between a hyperresponse to lutein and ß-carotene.

Once absorbed, cholesterol and carotenoids are incorporated into lipoproteins for transport in the blood. Several studies reported that total plasma cholesterol and its components, LDL and HDL, are correlated with plasma carotenoid concentrations (42–45). Carotenoids are not distributed equally among lipoproteins (46–49). The nonpolar carotenoids, ß-carotene and -carotene, are found predominantly in LDL with smaller amounts in HDL and VLDL. The polar carotenoids, lutein and zeaxanthin, are found in higher amounts in HDL than in LDL. Both HDL cholesterol and plasma lutein increased in male and female hyperresponders after the EGG treatment. This is consistent with the role of HDL as the primary carrier of lutein. Because the SUB treatment contained no cholesterol, the relation between the change in plasma cholesterol and the change in ß-carotene after the SUB period could not be determined.

Women had greater plasma concentrations of zeaxanthin, -carotene, and ß-carotene than men. Plasma lutein did not differ between men and women. Similar results occurred in population studies from several countries that reported higher plasma concentrations of provitamin A carotenoids in women than men, whereas the nonprovitamin A carotenoids, lutein, zeaxanthin, and lycopene were not consistently greater (21,24–26,42,44,50). It was suggested that lower plasma carotenoids in men are due primarily to lower consumption of carotenoid-rich foods by men compared with women (42). Although differences in the dietary habits of men and women are a major determinant of plasma carotenoids, this was not a significant factor in this study. The dietary intake of carotenoids did not differ in men and women.

The response to lutein after the EGG period did not differ between men and women. This is consistent with an earlier study in which the lutein concentrations in plasma of men and women did not differ after 4 mo of lutein supplementation (51). Although gender was not a factor in the lutein response, it was a significant factor in the ß-carotene response. Both men and women classified as hyperresponders to cholesterol had a significant increase in plasma ß-carotene after the SUB period, whereas their hyporesponsive counterparts were not affected. The increase in plasma ß-carotene after the SUB period in female hyperresponders (0.29 ± 0.48 µmol/L) was significantly greater than that in male hyperresponders (0.07 ± 0.07 µmol/L). This resulted in a significant interaction between gender and response for ß-carotene but not lutein. Similar gender differences occurred in a study with elderly subjects (67–93 y). Women were more responsive than men to dietary provitamin A carotenoids (-carotene, ß-carotene, ß-cryptoxanthin), but had an identical response to lutein and zeaxanthin (21).

In conclusion, responsiveness to dietary lutein and ß-carotene are associated with the plasma response to dietary cholesterol. Lutein and cholesterol responses are consistently related, whereas the ß-carotene response is more variable. Women exhibited a response to dietary lutein similar to that of men, but had a greater and more variable response to ß-carotene.

Until recently, carotenoids were thought to translocate across membranes by passive diffusion. Recent studies, demonstrating shared receptor-mediated uptake of carotenoids and cholesterol, explain in part the similarities in plasma responses (17–20). During et al. (19) suggested cellular trafficking of carotenoids, involving more than one transporter. Future research into the role of receptors in addition to SR-BI in controlling utilization of carotenoids in the body may help explain the heterogeneity of reponses that occur with these dietary components.

	FOOTNOTES

 
¹ Presented in part at Experimental Biology 04, April 2004, Washington, D.C. in abstract form [Clark RM, Herron KL, Waters D, Fernandez ML. Classification of the response to dietary cholesterol provided by eggs and gender predict lutein and zeaxanthin plasma concentrations (abstract). FASEB J. 2004;18:A156].

² Supported by the American Egg Board, The University of Connecticut Research Foundation, and grant NRI 02-35200-12312 from the U.S. Department of Agriculture.

⁴ Abbreviations used: apo, apolipoprotein; EGG: egg treatment; HDL-C: HDL cholesterol; LDL-C: LDL cholesterol; NCEP, National Cholesterol Education Program; SR-BI, scavenger receptor class B type; SUB: egg substitute treatment; TC: total cholesterol; TG: triglycerides.

Manuscript received 21 October 2005. Initial review completed 29 November 2005. Revision accepted 23 December 2005.

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