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Men Classified as Hypo- or Hyperresponders to Dietary Cholesterol Feeding Exhibit Differences in Lipoprotein Metabolism

Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269 and ^* Columbia University, New York, NY 10032

²To whom correspondence should be addressed. E-mail: kristin.herron{at}uconn.edu.

	ABSTRACT

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The purpose of this study was to evaluate the differences that occur within the plasma compartment of normolipidemic men, classified on the basis of their response to prolonged consumption of additional dietary cholesterol. Using a crossover design, 40 men aged 18–57 y were randomly allocated to an egg (640 mg/d additional dietary cholesterol) or placebo group (0 mg/d additional dietary cholesterol), for two 30-d periods, which were separated by a 3-wk washout period. Subjects were classified as hypo- [increase in plasma total cholesterol (TC) of <0.05 mmol/L for each additional 100 mg of dietary cholesterol consumed] or hyperresponders (increase in TC of 0.06 mmol/L for each additional 100 mg of dietary cholesterol consumed) on the basis of their plasma reaction to the additional dietary cholesterol provided. Male hyporesponders did not experience an increase in LDL cholesterol (LDL-C) or HDL cholesterol (HDL-C) during the egg period, whereas both lipoproteins were significantly (P < 0.0001 and P < 0.05, respectively) elevated in hyperresponders. Although the LDL/HDL ratio was increased in male hyperresponders after the high cholesterol period, the mean increase experienced by this population was still within National Cholesterol Education Program guidelines. Furthermore, male hyperresponders had higher lecithin cholesterol acyltransferase (P < 0.05) and cholesteryl ester transfer protein (P < 0.05) activities during the egg period, which suggests an increase in reverse cholesterol transport. These data suggest that additional dietary cholesterol does not increase the risk of developing an atherogenic lipoprotein profile in healthy men, regardless of their response classification.

KEY WORDS: • dietary cholesterol • metabolic response • men • lecithin:cholesterol acyltransferase • cholesteryl ester transfer protein

Dietary intake influences lipoprotein concentration, composition and metabolism, which can affect the development of atherosclerosis and coronary heart disease (CHD). Because CHD is the leading cause of death in the United States (1 ), it is important to examine the individual response to certain dietary components that have been implicated in disease progression.

Dietary cholesterol, and its relationship to plasma total cholesterol (TC) and the progression of chronic disease, has been examined extensively. Early studies (2 ,3 ) provided evidence, which remains consistent today, that increased consumption of dietary cholesterol can elevate TC values to some extent in certain individuals. Because increases in TC and LDL cholesterol (LDL-C) are established risk factors for CHD, recommendations to limit consumption of high cholesterol foods have been implemented in an attempt to prevent the progression of disease. A recent meta-analysis (4 ), which examined 17 studies in which experimental diets differed only in the amount of dietary cholesterol or the number of eggs consumed, found that one additional egg per day can increase the TC/HDL cholesterol (HDL-C) ratio by 0.040, causing a 2.1% increase in the risk for myocardial infarction. In contrast, a review (5 ) of multiple case-controlled studies, which measured intake of cholesterol and disease incidence, found that a relationship could not be clearly established between the dietary component and increase in CHD risk. Furthermore, data gathered from the Lipid Research Clinics Prevalence Follow-up Study (6 ), which examined both men and women (n = 4546), found that no significant relationship existed between deaths attributable to CHD and dietary cholesterol intake. Several studies have also failed to find an association between the incidence of CHD and egg consumption (7 –9 ). One explanation for this failure to connect elevated TC, experienced as a result of additional egg intake, to CHD incidence is that plasma changes may be due to increases in both LDL-C and HDL-C (10 ). This simultaneous increase allows for the maintenance of the LDL/HDL ratio, a strong predictor of CHD risk. Furthermore, eggs are a good source of essential amino acids, folate and other B vitamins, unsaturated fatty acids and -tocopherol, which may offset any harmful effects of the cholesterol provided (11 ).

Because individuals do not experience a uniform response to dietary cholesterol, it is difficult to accurately predict its effect on plasma TC and lipoprotein concentrations. Factors such as ethnicity, hormonal status, obesity, lipoprotein disorders and genetic predisposition (12 ,13 ) may explain this variation in response. Several meta-analyses (10 ,12 ,14 ), which examined the available data regarding the plasma lipid and lipoprotein response to dietary cholesterol, provided evidence that a modest increase in TC of 0.05–0.06 mmol/L may be predictable in response to a 100-mg increase in dietary cholesterol intake (4 ,15 ). If this moderate increase is used as a reference, those who experience elevations in TC of 0.065 mmol/L would be classified as hyperresponders to dietary cholesterol, whereas hyporesponders would be those who have no change in TC or experience increases of <0.05 mmol/L in response to a 100-mg increase in cholesterol intake. A previous examination of the plasma response to additional dietary cholesterol feeding in premenopausal women, which utilized this classification, revealed the presence of these two distinct populations (16 ).

The existence of a hypo- or hyperresponse to dietary cholesterol has been clearly established in various animal species (17 –19 ). The presence of a consistent and reproducible response to dietary cholesterol in men and women has also been found (20 ) and is considered to be determined by genetic factors (21 ,22 ). Mutations of several gene loci, such as the APOE and APOAIV (23 ), have been identified that may explain why some individuals are insensitive to dietary cholesterol, whereas others experience significant plasma compartment changes in response to intake. Furthermore, it has also been suggested that hyporesponders may have the ability to maintain cholesterol homeostasis by decreasing synthesis (24 ), absorption (25 ) or increasing biliary excretion (26 ,27 ) after increased intake of dietary cholesterol.

The main objective of this study was to further clarify the changes that occur within the plasma compartment of healthy men after prolonged consumption of additional dietary cholesterol. A second objective was to evaluate how those classified as hyperresponders process the excess cholesterol in the plasma compartment. Third, differences between the male and female response to dietary cholesterol were to be determined utilizing data previously gathered from an identical study with premenopausal women (16 ).

	SUBJECTS AND METHODS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Materials.

Liquid whole eggs and cholesterol/fat-free eggs (placebo) were purchased from Better Brands (Windsor, CT). Enzymatic TC and triglyceride (TG) kits were obtained from Roche-Diagnostics (Indianapolis, IN). Apolipoprotein (apo) C-III and apo E kits were ordered from Wako Pure Chemical (Osaka, Japan). Apo B kits, EDTA, aprotinin, sodium azide and phenylmethylsulfonyl fluoride (PMSF) were obtained from Sigma Chemical (St. Louis, MO).

Subjects.

Men (n = 40) between the ages of 20 and 50 y were recruited from the University community. The exclusion criteria for this study included the presence of hypercholesterolemia (TC >5.68 mmol/L), hypertriglyceridemia, hypertension and diabetes. Furthermore, those receiving lipid-lowering drugs were also excluded. Subjects had TC concentrations within the range of 3.62–5.17 mmol/L at baseline.

Experimental protocol.

The experimental protocol was approved by the University of Connecticut 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 or placebo group for 30 d, followed by a 3-wk washout period, after which the second dietary period began. Subjects assigned to the egg group were expected to consume the liquid equivalent of 3 whole eggs/d (640 mg/d dietary cholesterol). In contrast, the placebo group consumed an identical weight of egg substitutes (0 mg/d dietary cholesterol). The products were identical in terms of color and consistency, and differed only in the fat and cholesterol content. Daily amounts were provided in individual containers, and subjects were asked to return any uneaten portion at the end of the week.

Subjects 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. The NCEP Step I diet recommends that no >30% of total energy come from fat, with saturated fat providing only 10% of total fat. In addition, subjects were instructed to consume no >300 mg/d dietary cholesterol. To ensure compliance with the dietary guidelines, subjects completed seven 24-h dietary records during each treatment period, which included two weekend days. Nutrient intake was determined using the Nutrition Data System for Research (NDS-R) software version 4.0, developed by the Nutrition Coordinating Center, University of Minnesota, Minneapolis, MN, Food and Nutrient Database 28.

Two fasting (12 h) blood samples were initially collected, on different days, from each subject into tubes containing 0.10 g/100 g EDTA to determine baseline plasma lipids. Plasma was separated by centrifugation at 1500 x g for 20 min at 4°C, and placed into vials containing PMSF (0.05 g/100 g), sodium azide (0.01 g/100 g) and aprotinin (0.01 g/100 g). Two additional blood samples were collected and processed in the same manner at the end of each diet treatment and washout period. The variables of weight, blood pressure, level of activity, smoking and alcohol intake were also measured at baseline and after each dietary period to account for the possible influence of these factors on plasma lipid levels and lipoprotein metabolism.

Plasma lipids and apolipoproteins.

Our laboratory has participated in the Centers for Disease Control/National Heart, Lung and Blood Institute (CDC-NHLBI) Lipid Standardization Program since 1989 for quality control and standardization for plasma TC, HDL-C and TG assays. CV assessed by the standardization program during the study period were 0.76–1.42% for total cholesterol, 1.71–2.72% for HDL-C and 1.64–2.47% for triglycerides.

The effects of dietary cholesterol on TC, LDL-C, HDL-C and TG concentrations and the LDL/HDL ratio were examined. TC was determined by enzymatic methods using Roche-Diagnostics standards and kits (28 ). HDL-C was measured in the supernatant after precipitation of apo B-containing lipoproteins (29 ) and LDL-C was determined using the Friedewald equation (30 ). TG were determined using Roche-Diagnostics kits, which adjust for free glycerol. Means of the two blood draws were used to assess differences between treatment periods. Kits, which utilize an immunoturbidimetric method, were obtained from Sigma for the determination of apo B concentrations. Turbidity was measured in a microplate spectrophotometer at 340 nm (31 ). Apo C-III (32 ) and apo E (33 ) were measured with a Hitachi Autoanalyzer 740 utilizing kits from Wako.

Classification of hyper- and hyporesponders.

As previously mentioned, a modest increase in TC of 0.05–0.06 mmol/L may be considered normal in response to a 100-mg increase in dietary cholesterol. Therefore, for this study and the previous one conducted in premenopausal women (16 ), subjects who experienced an increase in total cholesterol 0.06 mmol/L for each additional 100 mg of dietary cholesterol were considered hyperresponders. Because the subjects were fed an additional 640 mg/d of dietary cholesterol, those who experienced an increase in TC of 0.41 mmol/L were considered hyperresponders. The remaining subjects who experienced fluctuations of <0.36 mmol/L (an increase in TC of <0.05 mmol/L for each additional 100 mg of dietary cholesterol consumed) or had no change in TC were identified as hyporesponders. The reproducibility of individual differences in response has been documented previously in several controlled and field trials (34 ).

Plasma CETP and LCAT.

Cholesteryl ester transfer protein (CETP) activity was determined in plasma according to the method described by Ogawa and Fielding (35 ). This method measures the mass transfer of cholesterol ester between HDL and apo B–containing lipoproteins. Thus, physiologic CETP activity was determined through an analysis of the decrease in HDL cholesterol ester mass between 0 and 6 h, without lecithin:cholesterol acyltransferase (LCAT) inhibition. Samples were incubated at 37°C for 6 h in a shaking water bath. After this period, total, HDL and plasma free cholesterol were measured, and previously described calculations were performed (36 ). LCAT activity was determined by an endogenous self-substrate method, which involves mass analysis of the decrease in plasma free cholesterol between 0 and 6 h at 37°C. Assays were carried out concurrently with measurements of CETP. Both of these methods have been standardized in our laboratory.

Data analysis.

Student’s t test was used to compare baseline characteristics of the two groups of men. Because subjects were separated into hyper- and hyporesponders after data collection, a paired t test was used to evaluate the changes in plasma lipids, apoproteins, CETP and LCAT activities that occurred within the response groups during the egg and placebo periods. A paired t test was also used to assess differences in the dietary consumption of macronutrients, dietary cholesterol, alcohol and dietary fiber.

	RESULTS

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Classification of the men’s responses to additional dietary cholesterol resulted in the identification of 25 hypo- and 15 hyperresponders (Fig. 1 ). Therefore, 62.5% of the men studied exhibited the hyporesponse, whereas only 37.5% were hyperresponders.

View larger version (13K): [in this window] [in a new window]   FIGURE 1 Changes in plasma total cholesterol in hypo- (n = 25) and hyperresponding (n = 15) men during the egg and placebo intake periods.

View larger version (45K): [in this window] [in a new window]   FIGURE 2 Plasma LDL and HDL cholesterol concentrations in men and premenopausal women during egg and placebo periods. Values are means ± SD for male hyperresponders (n = 15) and hyporesponders (n = 25) and female hyperresponders (n = 20) and hyporesponders (n = 31).**Significantly different from the placebo period (P < 0.001). NS, P > 0.05. Female data were adapted from Herron et al. (16 ).

View larger version (32K): [in this window] [in a new window]   FIGURE 3 Plasma LDL/HDL ratios in men and premenopausal women during egg and placebo periods. Values are means ± SD for male hyperresponders (n = 15) and hyporesponders (n = 25) and female hyperresponders (n = 20) and hyporesponders (n = 31).**Significantly different from the placebo period (P < 0.05). NS, P > 0.05. Female data were adapted from Herron et al. (16 ).

	DISCUSSION

TOP ABSTRACT SUBJECTS AND METHODS RESULTS DISCUSSION LITERATURE CITED

Dietary intake analysis.

The analysis of the self-reported dietary intake data indicated that both response groups complied with the NCEP step I diet requirements regarding cholesterol and fat intake during both treatment periods. The egg substitute given in this study, although it did contain the same quality and amount of protein, contained no fat or cholesterol. Therefore, the dietary variations observed can be attributed primarily to the eggs consumed. One whole egg provides 313.5 kJ, 1.5 g of SFA, 1.9 g of MUFA and 0.682 g of PUFA (37 ). Consequently, both hypo- and hyperresponders reported a significant elevation in the percentage of energy obtained from total fat during the egg period, with hyporesponders recording the greatest increase in consumption. Epidemiologic data clearly indicate that a strong positive relationship exists between the percentage of energy obtained from SFA and CHD incidence (38 ). It has been determined that a fluctuation in LDL-C of 0.120 mmol/L (4.6 mg/dL) can be expected for every 1% change in SFA intake with relation to the percentage of total energy consumed (12 ). Interestingly, hyporesponders were the only group that reported a significant increase (1.4% change) in the percentage of energy obtained from SFA during the egg period. However, their mean LDL-C level actually decreased, although not significantly, by 0.04 mmol/L (1.5 mg/dL). It has also been determined previously that diets that replace SFA with MUFA and PUFA result in a decrease in plasma LDL-C concentrations (39 ). One study (40 ) found that replacing SFA with MUFA resulted in decreases of 12% in TC and 15% in LDL-C levels. In addition, MUFA-rich LDL particles have been shown to be less susceptible to oxidation than those enriched with PUFA (41 ). In this study, hyperresponders were the only group that reported a significant (P < 0.05) increase in MUFA intake during the egg period. These findings suggest that the fluctuations seen in the plasma compartment are independently driven by the egg’s contribution of cholesterol to the diet.

Plasma compartment changes.

It has been reported that gender does not affect the plasma response to dietary cholesterol consumption (20 ). Therefore, the men in this study were expected to experience changes in the plasma compartment similar to those examined previously in premenopausal women subjected to the same experimental conditions (16 ). During the high cholesterol period, male hyperresponders experienced significant increases in LDL-C, HDL-C and the activities of LCAT and CETP. Female hyperresponders also experienced significant increases in LDL-C, HDL-C and CETP activity after the dietary cholesterol challenge. Furthermore, female hyperresponders had elevated LCAT activity, regardless of dietary treatment. The higher concentrations and activity levels of these variables suggest that hyperresponders, regardless of gender, enhance the reverse cholesterol transport pathway to mobilize the excess cholesterol to the liver, the major site of cholesterol elimination from the body.

Peripheral cells cannot degrade sterols; therefore, they rely on the transfer of neutral lipids to lipoproteins. Excess free cholesterol, collected by HDL, must be esterified immediately by LCAT to preserve the hydrophilic nature of the particle and to maintain the concentration gradient for further intake (42 ). The cholesteryl ester (CE) in the HDL particle has an alternate fate as well. CE can be transferred to the apo B–containing lipoproteins in exchange for triglycerides. This transfer is mediated by CETP. Because increased CETP activity promotes this enrichment of circulating apo B–containing lipoproteins with CE, and is usually associated with a decrease in HDL-C, it is regarded as proatherogenic (43 ). However, if an increase in CETP is not related to a decrease in HDL-C, the protein appears to function in an antiatherogenic manner by enhancing the enrichment of LDL particles that can be taken up by the liver, where the cholesterol ester components are metabolized (44 ). This process represents an indirect pathway of reverse cholesterol transport that may be enhanced in some individuals in response to increased dietary cholesterol intake. Other studies (45 ) have provided evidence suggesting that dietary cholesterol consumption does not inhibit the reverse cholesterol transport pathway, but in fact enhances cholesterol efflux from cells.

Of particular concern in the present study was that the male population had elevations in LDL-C after egg intake that were not offset by the higher HDL-C concentrations, and therefore the LDL/HDL ratio was increased. Several previous studies (46 –50 ) found that a beneficial LDL/HDL ratio can be maintained after egg consumption. Although this was not the case in the men in this study, the mean was still <3.25, which is considered to be correlated with low risk for CHD according to the updated clinical guidelines of the NCEP adult treatment panel III (51 ).

The atherogenicity of the LDL particle is also an important indicator of CHD risk. LDL particles are heterogeneous with regard to size, density, composition, charge and atherogenicity (52 ). Small, dense LDL particles, identified as the pattern B subclass, are considered to be more atherogenic than the larger CE-enriched fraction (53 ). A predominance of LDL particles in this pattern B subclass has been shown to be associated with a threefold increase in CHD risk (54 ,55 ), which may be due to the easy entry of the particle into the arterial wall and its high susceptibility to oxidation. We speculated that because the increase in LDL-C in hyperresponders was not accompanied by an elevation in the measured plasma apo B concentration, this population may have a predominance of the larger, less atherogenic lipoprotein particles after the dietary cholesterol challenge. This is based on the understanding that one apo B is present on each particle, and therefore maintenance of the apoprotein concentration indicates that the increase in LDL-C may not be due to an increase in the number of circulating particles, but to an increase in the size of the lipoprotein.

These results indicate that premenopausal women and men with initial plasma cholesterol concentrations that place them at a low risk for CHD do not develop an atherogenic lipoprotein profile after the consumption of additional dietary cholesterol, regardless of their response classification. It is important to note that the men who participated in this study happened to have low baseline TC values, and therefore were not a representative sample of the overall male population of the United States. This was a random occurrence in that the men were recruited from the University community and no subjects who volunteered were ineligible for participation. It is possible that individuals with higher TC concentrations may respond differently to the same dietary treatment.

	ACKNOWLEDGMENTS

 
Special thanks are extended to Dolores Silbart, our phlebotomist, for her time and effort.

	FOOTNOTES

 
¹ K.L.H. is the 2002 recipient of the American Egg Board Egg Nutrition Center Dissertation Fellowship in Nutrition.

³ Abreviations used: apo, apolipoprotein; BMI, body mass index; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; CHD, coronary heart disease; HDL-C, HDL cholesterol; LCAT, lecithin:cholesterol acyltransferase; LDL-C, LDL cholesterol; NCEP, National Cholesterol Education Program; PMSF, phenylmethylsulfonyl fluoride; SFA, saturated fatty acid; TC, plasma total cholesterol; TG, triglyceride.

Manuscript received 3 September 2002. Initial review completed 8 November 2002. Revision accepted 18 December 2002.

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