| | Sex-dependent variables in the modulation of postalimentary lipemiaReceived 15 December 2004; received in revised form 3 May 2005 published online 13 October 2005. Abstract ObjectiveTo quantify in young adults the sex-dependent differences in lipemic responses to a fat meal, we measured the association of these responses with markers of atherosclerosis and determined their metabolic regulators. MethodsForty-nine normolipidemic volunteers, 25 women and 24 men, were matched according to age, body mass index, waist circumference, diet, physical activity, and apolipoprotein-E phenotyping. After receiving a standardized fat meal (40 g of fat/m2 of body surface area), serial blood samples were drawn for laboratory analysis. Common carotid intima-media thickness was measured. ResultsThe lipemic responses were much greater in men than in women for plasma triacylglycerol (TAG), cholesterol, and TAG in TAG-rich lipoproteins, non-esterified fatty acids, phospholipids, and apolipoprotein-B100. Men presented with increased blood pressure, carotid intima-media thickness, TAG, hepatic lipase, and insulin and lower high-density lipoprotein cholesterol, apolipoprotein-AI, and non-esterified fatty acid concentrations. Only in men did carotid intima-media thickness correlate marginally with titers of autoantibodies to epitopes of oxidized low-density lipoprotein; in addition, phospholipids and cholesteryl esters were negatively related to autoantibodies. Multivariate analysis indicated that age (R2 = 45%), waist circumference (R2 = 19%), phospholipids (R2 = 39%), non-esterified fatty acids (R2 = 29%), insulin (R2 = 17%), lipoprotein lipase activity (R2 = 16%), and cholesteryl ester transfer protein (an exploratory variable; R2 = 6%) are strong determinants of postalimentary lipemia in women and that only insulin (R2 = 55%) and phospholipids (R2 = 37%) are determinants in men. ConclusionsWe have provided data explaining that postalimentary lipemia is differently regulated by sex. Several risk factors for coronary heart disease and significant associations with atherosclerosis biomarkers were found only in men.
Introduction  Increased postalimentary lipemia has been positively associated with risk for developing coronary heart disease. In part, this may be explained by slower removal of triacylglycerol-rich lipoproteins (TRLs) in the postalimentary period and their deposition in the subendothelial region of the arterial wall, the formation of atherogenic small dense low-density lipoprotein (LDL) particles, and a decrease in the concentration of cardioprotective high-density lipoproteins (HDLs) [1], [2], [3], [4]. Moreover, postalimentary lipemia interacts with the thrombotic process in which an increased concentration of postalimentary TRL has the ability to activate coagulation factor VII and plasminogen activator inhibitor [3]. The prevalence of coronary heart disease in men is higher than that in women before menopause and that after menopause the prevalence in women approaches that in men [5], [6], [7]. While the causes are not completely understood, estrogens have been found to favorably affect several aspects of cardiovascular disease, the plasma lipid profile [8], degree of oxidation of LDL [9], and endothelial function [10]. Postalimentary lipid metabolism differs between the sexes and men present with higher lipemia [11], [12], [13]. The complete regulation of this increased response is not well known. Some investigators have associated it with increased TRL production and decreased plasma clearance [11], [12]. Increased visceral fat in men has been suggested as an important contributing factor [13], [14]. The major aim of this study was to determine which metabolic variables were responsible for the sex differences in postalimentary lipemia. To achieve this goal, a standardized fat meal was administered to 25 healthy women and 24 healthy men, and blood samples drawn over 8 h. The ultrasound measurement of the common carotid was used to assess early stages of atherosclerosis and autoantibodies to epitopes of oxidized LDL to monitor the degree of LDL oxidation. Material and methods Forty-nine healthy volunteers, 25 women and 24 men, who were 19 to 45 y of age, were normolipidemic according to the National Cholesterol Education Program [15], and had no cardiovascular risk factors or established coronary heart disease were selected. They answered a questionnaire containing information on diet, physical exercise, use of tobacco, alcohol, and familial history of coronary heart disease. All procedures followed were in accordance with the research ethics committee of the School of Medicine of the State University of Campinas, São Paulo. These individuals underwent an oral fat tolerance test. The test began by venous puncture after a 12-h fast followed by ingestion of a milkshake prepared with lactose-free powdered milk (NAN, Nestlé, São Paulo, Brazil). The liquid meal contained fat (25%), dextromaltose (55%), protein (14%), and vitamins and minerals (6%), providing 40 g of fat per square meter of body surface, and was given over a period up to 10 min. Serial blood samples were collected at 2, 4, 6, and 8 h after ingestion. Measurements were performed on samples from all time points or from the TAG peak and/or 8 h. TRLs at a density lower than 1.006 g/L were isolated by sequential ultracentrifugation for 16 h at 4°C and 40000 rpm in a Beckman centrifuge (model L5-75B, Beckman, Palo Alto, CA, USA). Cholesterol (Chol) and triacylglycerol (TAG) in sera and in TRL particles were measured by enzymatic-colorimetric methods at all times (Hitachi 917, Roche, Mannheim, Germany); LDL-Chol and HDL-Chol were analyzed by a homogeneous direct enzymatic-colorimetric method. Fasting HDL subfractions (HDL2 and HDL3) were obtained by sequential micro-ultracentrifugation of the supernatants that were obtained after precipitation of lipoprotein containing apolipoprotein (Apo) B100 with dextran sulfate (Beckman micro-ultracentrifuge), with posterior Chol and TAG quantification by enzymatic-colorimetric methods. Apo-AI, Apo-B100, and lipoprotein(a) were analyzed by nephelometry. Non-esterified fatty acids (NEFAs), phospholipids (PLs), and free cholesterol (FC) through enzymatic-colorimetric methods (Waco, Osaka, Japan). Cholesteryl esters (CEs) were estimated by the difference between Chol and FC. Insulin was measured by an immunometric assay (Immulite/DPC/Medlab, Los Angeles, CA, USA). Lipoprotein lipase (LPL) and hepatic lipase (HL) activities were measured in fasted postheparin plasma samples on the basis of fatty acid release by using a radiolabeled triolein emulsion as the substrate and NaCl (1 M) as the LPL inhibitor, with results expressed as nanomoles of NEFA per milliliter per hour [16]. CE transfer protein (CETP) activity was determined by an exogenous assay that measures the transfer of radiolabeled CE between a normal donor pool of 14CE-HDL and an unlabeled acceptor mixture of very low-density lipoproteins (VLDL) plus LDL over 4 h by using plasma as the CETP source, and results are expressed as percentages of CE transferred [17]. The PL transfer protein (PLTP) was measured by an exogenous radiometric method using PL liposomes as the substrate [18] and an HDL pool, obtained from plasma donors, as the acceptor. Activity was expressed as the rate of radioactively labeled PL transfer per hour. Assays for CETP, PLTP, and lipase activities were conducted in triplicate. Interassay coefficients of variation were 12%, 2%, 9%, and 8% respectively for CETP, PLTP, LPL, and HL, respectively. Genomic DNA was obtained from peripheral blood samples by conventional methods. Restriction analysis of Apo-E polymorphism fragments amplified by polymerase chain reaction was performed as previously reported [19], [20]. The autoantibodies to epitopes of oxidized LDL were evaluated in all participants by enzyme-linked immunosorbent assay after samples were incubated with copper-oxidized LDL [21]. Results are presented as percentages of the optical density (OD) readings relative to the group ranked values. The carotid intima-media thickness (IMT) was measured by ultrasonography using the HDI 1500 Ultrasound System equipment (ATL Ultrasound, Bothell, WA, USA), with a 7- to 12-MHz color Doppler probe. The carotid IMT was calculated as the mean of five measurements in the far wall from the left and right common carotid arteries according to a standardized method [22], [23]. Individual results were expressed in millimeters as an average of the left and right carotid IMT. The significance level was 5%. The variables insulin, TAG, FC, NEFA, CETP, autoantibodies of oxidized LDL, TRL Chol and TAG, and TAG acquisition rate, TAG removal rate, TAG area under the curve (AUC), and area under the incremental curve (AUIC) were log transformed. The trapezoidal method was used for estimation of the AUCs and AUICs. Slopes of the individual curves were determined by linear regression analysis and expressed as the acquisition rate, from 0h to TAG peak, and as the removal rate, from peak to the time with the lowest TAG concentration. Repeated measures analysis of variance with post hoc Tukey’s and/or the profile test were used for evaluation of postalimentary responses with time, differences between sexes, and interaction of time and sex. Chi-square and Fisher’s exact tests were used for categorical variables. Student’s t test was used to compare the summary measurements of curves and slopes. Pearson’s correlation with Bonferroni’s correction related the variables in each sex. Hierarchical multiple linear regression analysis with stepwise criteria for selection of variables was used to assess the influence of specific plasma factors on postalimentary lipemia, as the summary measurements of curves. Results are expressed as coefficients of determination (R2) that represent percentages of variation in the dependent variables (TAG AUC, AUIC, acquisition rate, and removal rate) explained by the independent variables (age, waist circumference [WC], body mass index, diet, physical activity, Apo-E genotyping, insulin, PLTP, HL, LPL, CETP, NEFA AUC and AUIC, and PL AUC and AUIC). Results Baseline parameters Anthropometric and metabolic characteristics of the participants are presented in Table 1. Participants were young adults (31 ± 8 y for women and 27 ± 6 y for men) who were matched by age, WC, body mass index, diastolic blood pressure, and diet and exercise (not shown). Systolic blood pressure and carotid IMT were higher in men (Table 1). All biochemical baseline analyses were within reference limits. Women presented increased levels of HDL-Chol, HDL3-Chol, Apo-AI, and NEFA and decreased TAG level (32–141 mg/dL in women and 32–158 mg/dL in men) and HL activity when compared with men. The Apo-E genotypes were not different between the sexes (P = 0.316, not shown). The distributions of alleles were 1 E2/E3, 1 E2/E4, 13 E3/E3, and 7 E3/E4 for women and 5 E2/E3, 2 E2/E4, 12 E3/E3, 4 E3/E4, and 1 E4/E4 for men. Postalimentary parameters Plasma TAG level increased and reached its peak approximately 4 h after the meal with equal magnitude in women and men (109 ± 46 and 153 ± 86 mg/dL, respectively; Fig. 1A); TAG and Chol in TRL were increased at 2 h (Fig. 1B,C). Postalimentary values were reached at 8 h for TAG and TAG TRL and after 8 h for Chol TRL. AUCs were larger in men for TAG, TAG TRL, and Chol TRL (Fig. 1A–C). In men, TAG was increased at baseline and at 2 and 6 h and TAG TRL and Chol TRL at baseline and at 2, 4, and 6 h compared with women. There was also a decrease in HDL-Chol and Apo-AI at all times (not shown). In men, HDL-Chol decreased at 2, 4, and 6 h and Apo-AI at 4 h (not shown). The HDL-Chol acquisition rate was 75% lower in men than in women (not shown). A significant increase was verified after the meal for TAG and TAG TRL at all times and for Chol TRL at the 2, 4, and 6 h in men and women (Fig. 1A–C). Significantly decreased NEFAs was observed at 2, 4, and 6 h from baseline in women; in men, NEFAs increased at 6 and 8 h from baseline. In women, NEFAs were higher at baseline and lower at 6 h compared with men (Fig. 2A). PL and NEFA AUICs were larger in men than in women (Fig. 2A,B). PL concentration was similar between men and women. It increased at all times from baseline in men; in women, the increase occurred at 4 and 8 h from baseline (Fig. 2B). Fasting CETP activity showed no sex differences, except for an increase at 4 h (after diet) in men only (Fig. 2C). Insulin levels did not present significant differences between men and women during the fasting period but did decrease at 4 h in men compared with women. The response was present in men and women from baseline values (Fig. 2D). Women presented FC-positive responses at all times and decreased levels of total Chol at 6 h from baseline. Men had higher levels of FC and lower level of total Chol at 4 and 6 h compared with the fasting period. Apo-B100 decreases at 2, 4, and 6 h were seen in men. No postalimentary differences were found between men and women for Chol, LDL-Chol, FC, CE, Apo-B100, and lipoprotein(a) (not shown). In men acquisition rates were higher for NEFA and lower for HDL-Chol. The removal rate was lower for TAG TRL and NEFA. Relations of postalimentary TAG to common carotid IMT, autoantibodies to epitopes of oxidized LDL, and other metabolic variables There were significant associations of postalimentary TAG responses to PL (r = 0.63, P = 0.0007) in women and to insulin (r = 0.77, P = 0.0001) and PL (r = 0.65, P = 0.0007) in men. There were no associations of IMT with the parameters of TAG summary measurements of curves in either sex. In men IMT correlated with FC (r = 0.52, P = 0.01). Interestingly, only in men there was a borderline correlation between autoantibodies to oxidized LDL at 8 h and IMT (r = 0.48, P = 0.03). In women there were associations of antibodies to oxidized LDL with TAG at 8 h (r = 0.69, P = 0.002), Chol TRL at 2 h (r = 0.74, P = 0.001), FC at 0 h (r = 0.63, P = 0.005), and CETP at 0 h (r = −0.71, P = 0.001, negative). In men the correlations were negative with CE (r = −0.53, P = 0.007) and PL at 2 h (r = −0.57, P = 0.003). Multivariate analysis of relations of several metabolic variables to measurements of postalimentary TAG responses To evaluate whether some of the observed relations in the univariate analysis were important to explain sex differences and were independent of each other, these effects (in women and men) were studied by multiple linear regression analysis and stepwise method (Table 2). Because of the number of dependent variables for TAG AUIC in women (Table 2), the results for this dependent variable acquired an exploratory nature. Postalimentary lipemia was determined in women by age (inverse), insulin, PL, NEFA, CETP (suggested), WC, and fasting LPL (strongly suggestive) and in men by insulin and PL. The strongest predictors of postalimentary lipemia in women were age (45%), PL (39%), and NEFA (29%), with WC (19%) and insulin (17%) accounting for a smaller contribution. In men, insulin accounted for 55% and PL for 37% of the response. Discussion This study investigated the factors that modulate postalimentary lipemia in women and men [11], [24]. The main finding was that women presented a more complex regulation of postalimentary lipemia than did men, with a wider number of explanatory variables, some of them peculiar to women. Age, WC, NEFA, PL, and insulin were the main determinants in women that accounted for an important proportion of the variation in lipemia. CETP and LPL (negatively) were secondary modulators in women. In men the regulators were insulin and PL, which were shared with women. Sex differences in postalimentary lipemia have been reported by several investigators, with men presenting increased TAG responses [25], [26]. Compared with women, the higher postalimentary lipemia observed in men in this work was explained by increased Chol and TAG in TRL, giving rise to an atherogenic postalimentary profile. A higher rate of TRL production of intestinal and hepatic origin [27] could be the explanation for this enhancement. It has been shown that production of VLDL can be lower in women because they suppress more circulating NEFA concentrations after an oral glucose tolerance test [28]. Another possible explanation for the increased lipemia could be the delayed catabolism of TRL by LPL and by the liver [29]. The increased HL activity and the decreased removal rate of TRL in men in this study points to a decreased receptor TAG-rich particle affinity in the liver. LPL was similar in men and women and differences in Apo-E genotyping did not explain the different types of lipemia, which is in accordance with other studies in the literature [30]. Insulin level was similar in women and men during the fasting period, and higher levels were found in women 4 h after the meal. Insulin modulated lipemia in both sexes. Insulin acts on lipoprotein metabolism in several ways: by increasing lipogenesis and decreasing lipolysis in adipose tissue, decreasing the pool of circulating NEFAs, decreasing VLDL production by the liver from NEFA, and activating LPL. The NEFA plasma pool reflects in part insulin activity. Women had increased fasting NEFA levels [31]. We could postulate in this study that men responded to a fat meal with an insulin-resistant profile, and this was indicated by a lower insulin concentration at 4 h and higher NEFA concentrations at 6 h compared with women. Men also presented larger NEFA postalimentary AUICs and higher acquisition rates [5]. The larger NEFA flux in men could interfere with the lipolytic process by remnant formation [32]. The mechanisms underlying these findings could be an enhanced ability to activate hormone-sensitive lipase in visceral fat cells in men and a consequent increased flux in plasma NEFA and to the liver followed by VLDL production [33]. In contrast, women showed a decreased NEFA response to the meal, which is consistent with more efficient plasma NEFA extraction. Phospholipidemia was a strong determinant of lipemia in men and women. PLs are the major component of HDL and this factor indirectly indicates a regulation by HDL. There is an inverse ratio between TAG and HDL-Chol because HDL is partly produced in plasma through the hydrolysis of TRL [34]. The minor modulators, LPL and CETP, have well-established actions in TAG-rich lipoprotein metabolism [32], the first favoring TRL catabolism and the second shifting the transfer of CE to TRL and to LDL receptors in the liver. CETP was similar in men and women during the fasting and postalimentary periods, but men responded to the meal by increasing the activity of CETP. This finding may reflect the increased amount of TRL, CE acceptors in the transfer process mediated by CETP, in the postalimentary period in men. The lack of response in women may reflect the decreased pool of CE acceptors. LPL is a classic lipolytic enzyme that has as substrates TAG from TRL. In this study it modulated lipemia only in women, showing a resistant state to lipolysis in men. Also in women the WC, an indirect measurement of visceral fat, may explain the lipemia. Some studies have shown that visceral fat [13], [35] and age [36] regulate postalimentary lipemia; in this work the TAG clearance was negatively modulated by age only in women. Because sex, age, Chol, and some genotypes are determinants of carotid IMT [37], [38], the two groups were paired for age, Apo-E genotypes, and LDL-Chol. The classic associations of IMT with LDL-Chol were found in women, but an association of postalimentary TAG with IMT was observed only in men. Although young, the men had increased carotid IMT in relation to the women, indicating early atherosclerosis. Only in men were markers of lipemia negatively related to autoantibody levels, probably as result of an increased formation of immune complexes with oxidized LDL. In addition, the men in this study presented higher blood pressure, increased fasting TAG level, increased postalimentary lipemia, decreased HDL-Chol and Apo-AI levels, and increased HL activity. All these findings contribute to their higher risk of coronary heart disease. Their larger carotid IMT points to early atherosclerosis. The complex and more favorable interplay of variables in women generates a metabolic profile with a lower accumulation of postalimentary atherogenic particles, probably due in part to different levels of sex hormones [39]. Further studies should aim at better understanding the sex differences in lipemia regulation. 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a Department of Clinical Pathology, Faculty of Medicine Sciences and NMCE-UNICAMP, Campinas, São Paulo, São Paulo, Brazil b Laboratory of Lipids Faculty of Medical, University of São Paulo, São Paulo, São Paulo, Brazil c Diagnostic Image Laboratory, Campinas, São Paulo, São Paulo, Brazil d Laboratory of Immunophysiopathology, ICB, University of São Paulo and IMT-SP, São Paulo, São Paulo, Brazil  Corresponding author. Tel.: +00-55-19-3788-7064; fax: +00-55-19-3788-9434.
This work was supported in part by grants from the Fundação de Amparo à Pesquisa do Estado de São Paulo, Fundo de Apoio ao Ensino e Pesquisa da Universidade de Campinas, and Coordenadoria de Pessoal de Ensino Superior. PII: S0899-9007(05)00227-3 doi:10.1016/j.nut.2005.05.004 © 2006 Elsevier Inc. All rights reserved. | |
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