© 1996 American Heart Association, Inc.
Articles |
Relationship of Plasma Cholesteryl Ester Transfer Protein to HDL Cholesterol
Studies in Normotriglyceridemia and Moderate Hypertriglyceridemia
the Department of Internal Medicine, University of Innsbruck, Austria (B.F., A.R., A.D., J.R.P.), and the Department of Education, University of Berlin, Germany (H.W.).
Correspondence to Bernhard Foger, MD, Department of Internal Medicine, University of Innsbruck, Anichstraße 35, A-6020 Innsbruck, Austria.
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Abstract |
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To evaluate the independent effect of cholesteryl ester transfer protein (CETP) on HDL concentrations in humans, we measured lipids, lipoproteins, postprandial lipemia after an oral fat load, CETP mass, and the activities of CETP, lipoprotein lipase (LPL), and hepatic lipase in 16 healthy, normotriglyceridemic men and in 23 men with moderate, primary hypertriglyceridemia on an American Heart Association Step I diet. Fasting triglycerides and postprandial lipemia were increased and HDL cholesterol (HDL-C) was decreased in hypertriglyceridemic men compared with control subjects (P<.001). In the normotriglyceridemic group, CETP mass (P<.001) and activity (P<.005) were directly related to LPL activity After statistical adjustment for this close association, no significant relationship of CETP to HDL-C independent of LPL activity could be demonstrated in the normotriglyceridemic subjects. In contrast, CETP was unrelated to LPL activity in the hypertriglyceridemic subjects, but CETP concentrations showed a close inverse relationship to HDL-C (r=-.504, P=.014). Structural equation modeling of the association structures between HDL and fasting and postprandial triglycerides, endothelial lipases, and CETP in both groups indicated that the overall regression models for the two groups differed (P<.05). Specifically, the associations between CETP mass and activity and HDL-C differed between both groups (both P<.01). We conclude that high-normal CETP levels lower HDL-C in nonsmoking, nonobese men with moderate, primary hypertriglyceridemia on a hypolipidemic diet, but not in healthy, normotriglyceridemic men on an unrestricted diet. Thus, variation in CETP plasma concentrations may contribute to the high-triglyceride, low-HDL phenotype.
Key Words: triglycerides • HDL cholesterol • postprandial lipemia • lipoprotein lipase • cholesteryl ester transfer protein
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Introduction |
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A low HDL-C level is a powerful independent indicator of a high cardiovascular risk.1 Low HDL-C may promote atherogenesis via a reduced cholesterol transport from the artery wall to the liver.2 Small HDL precursor particles, ie, complexes of apoA and lipids, acquire unesterified cholesterol (and phospholipids) either from cellular membranes or from TGRLPs undergoing lipolysis through the action of LPL.3 Subsequently, lecithin:cholesterol acyltransferaseesterifies unesterified cholesterol on the HDL surface,2 resulting in the formation of an apolar core as CEs are formed. HDL CEs may either be returned to the liver, or, alternatively, be diverted to TGRLPs in exchange for their major core lipid, ie, TG, in a process catalyzed by CETP.4 HDL TGs may subsequently be hydrolyzed by HL, resulting in a reduction of the HDL core size and the conversion of larger HDL2 to smaller HDL3 particles.5 6 Thus, processes that augment HDL mass (driven by LPL and lecithin:cholesterol acyltransferase) are balanced by processes that reduce HDL mass by the combined actions and interactions of postabsorptive and postprandial TGRLPs, CETP, and HL. Because we are interested in identifying the factors that control HDL levels, we investigated whether, and if so, in which situations, HDL-C levels are related to CETP plasma concentrations.
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Methods |
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Subjects
Thirty-nine men, aged 21 to 68 years, gave informed consent for this study: 16 healthy, normotriglyceridemic men (TG<1.92 mmol/L) and 23 men with moderate, primary hypertriglyceridemia (TG>1.92 mmol/L). Exclusion criteria included smoking, frank obesity (BMI>30 kg/m2), alcohol abuse, long-distance running, use of ß-blockers or lipid-lowering drugs, unstable angina, heart failure, recent myocardial infarction, diabetes, or hepatic, gastrointestinal, renal, or endocrine disease as ascertained by patient history, physical examination, and determination of glucose, aminotransferases, creatinine, and thyroid-stimulating hormone in fasting plasma and glucose and protein in urine, respectively. Patients suffering from type I, dysbetalipoproteinemia or type III and type V hyperlipoproteinemia as determined by patient history, clinical examination, lipoprotein electrophoresis on agarose gels and apoE phenotyping, were also excluded from the study. The apoE phenotype distribution was 10 E3/3, 4 E3/2, and 2 E4/3 in the normotriglyceridemic group and 13 E3/3, 3 E3/2, 6 E4/4, and 1 E4/4 in the hypertriglyceridemic group. The normotriglyceridemic men showed no evidence of cardiovascular disease and were not on any medication. Of the 23 hypertriglyceridemic men, 9 had manifest coronary heart disease, but none presented with unstable angina, heart failure, or had experienced a myocardial infarction within the 6 months preceding the study. They were treated with aspirin, nitrates, calcium channel–blocking agents, angiotensin-converting enzyme inhibitors, and allopurinol. No ß-blockers or lipid-lowering drugs were used. The normotriglyceridemic men consumed an unrestricted diet that closely resembled that of the general Austrian population. The hypertriglyceridemic men were on an American Heart Association Step I diet7 for at least 6 weeks before the study. According to 72-hour dietary recalls, normotriglyceridemic and hypertriglyceridemic men, respectively, derived 14.5±2.5% and 14.4±2.3% of calories from protein (P>.10), 42.5±7.4% and 59.4±5.6% from carbohydrates (P<.001), and 43±7.2% and 26.2±3.7% from fat (P<.001), with polyunsaturated/saturated fat ratios of 0.50±0.25 and 1.1±0.5 (P<.001). Daily cholesterol intake averaged 379±132 and 218±69 mg in normotriglyceridemic and hypertriglyceridemic men, respectively (P<.001).
Blood Tests
Blood was drawn after an overnight fast from an antecubital vein into vials containing EDTA (final concentration, 1 g/L). Cholesterol and TG levels were determined by using enzymatic methods (Cholesterol PAP, MA-kit 100, and Triglyceride PAP, Uni-Kit III, Roche). HDL-C in fasting plasma was determined by using a precipitation procedure with dextran sulfate and magnesium chloride.8 ApoA-I and apoB were determined by using immunoturbidimetric tests (Tina-quant, Boehringer Mannheim). For all the above procedures a Cobas Mira Autoanalyzer (Roche) was used. ApoA-II was determined by using radial immunodiffusion (Immuno AG). ApoE phenotypes were determined by isoelectric focusing of delipidated plasma, Western blotting, and immunostaining.9
Zonal Ultracentrifugation
Two 10-mL aliquots of postabsorptive plasma were subjected to rate-zonal ultracentrifugation in a Ti 14 rotor at 42 000 rpm and 15° for 140 minutes using a linear NaBr gradient (d=1.0 to 1.3 kg/L) to separate VLDL, IDL, and LDL and for 22 hours using a discontinuous NaBr gradient (d=1.0 to 1.4 kg/L) to separate HDL2 and HDL3, respectively.10 By determining protein,11 TGs, CEs, free cholesterol (Boehringer Mannheim), and phospholipids12 in zonal rotor fractions representing VLDL, IDL, LDL, HDL2, and HDL3, the levels and compositions of the respective lipoproteins were obtained.
Postprandial Lipemia
Immediately after the postabsorptive plasma specimen was collected, probands ingested a liquid fatty meal.13 Briefly, the test meal contained, per square meter of body surface, 65.0 g fat with a polyunsaturated/saturated fat ratio of 0.06, 24 g carbohydrate, 4.75 g protein, and 240 mg cholesterol. TG levels were determined at 0, 2, 4, 6, 8, and 10 hours postprandially. The magnitude of postprandial lipemia was quantified as the area between two lines: the upper one connecting individual postprandial TG values and the lower one originating at the 0-hour level parallel to the abscissa at the fasting TG level. The magnitude of postprandial lipemia was thus normalized for the fasting TG level.13 14
LPL, HL, and CETP
After an overnight fast, probands were injected with heparin (2.280 U/m2 IV; Novo Industry A/S) to release LPL and HL into the circulation. Plasma was collected 10 minutes after the heparin injection. Sonicated emulsions of [9,10(n)-3H]oleic acid–labeled trioleoylglycerol (Amersham) in phosphatidylcholine and gum arabic were employed as substrates for estimation of the activities of LPL and HL, respectively.15 Heat-inactivated serum from postabsorptive rats was added as a source of apoC-II to LPL assay mixtures; HL was inhibited by goat anti-human HL IgG. To assay for HL activity, LPL was inhibited by raising the NaCl concentration of the incubation mixture to 1 mol/L and omitting the source of apoC-II. Incubation was performed at 25°C for 30 minutes.16 Activity is expressed in units per liter, which correspond to 1 µmol fatty acids released per minute per liter of postheparin plasma.
CETP activity was determined as described by Groener et al17 by using a substrate-independent isotope assay that measured radiolabeled CE transfer from exogenous LDL to exogenous HDL, mediated by a fraction of the respective probands' fasting plasma from which VLDL and LDL had been removed prior to the assay procedure. CETP mass was quantified by using an immunoradiometric assay employing a polyclonal antibody.18
Statistical Analysis
SPSS-X (release 4) software (SPSS) was used. Values are expressed as mean±SD. Variables were examined by using the Shapiro-Wilks and Lilliefors statistics to ascertain normality and by the Levene statistic to ascertain homogeneity of variances between the normotriglyceridemic and hypertriglyceridemic groups, respectively. When these preconditions for further parametric analyses were not met, variables were transformed appropriately, and normal distribution and homogeneity of variances were confirmed before statistical testing. Logarithmic transformations were used for TGs, HDL-C, apoA-I, postprandial lipemia, HDL subfraction levels, weight-percentages of TGs in zonal rotor fractions, and ratios of TGs/CEs, TGs/protein, and CEs/protein in zonal rotor fractions. All other variables were used untransformed. Between-group comparisons were performed by using Student's t test for independent samples. Relationships between variables are presented as Pearson correlation coefficients in the normotriglyceridemic and hypertriglyceridemic groups. P<.05 (two-tailed) was considered significant for between-group comparisons and for univariate and partial correlation analysis. To allow statistical comparison of Pearson correlation coefficients between the two study groups, we subjected the r values obtained for each relationship in each group to Fisher's transformation to Z.19 The resulting values were then transformed into a standard normal score that can be interpreted with the usual significance boundaries (±1.96 for 
=5%, two-tailed).20 Structural equation modeling was performed by using the "Analysis of Moment Structures" computer program.21 The structural equation models generated were evaluated by using 
2 goodness-of-fit tests. In these tests, a nonsignificant statistic for the model indicates that the observed data and the specified model do not differ significantly. Significant tests, on the other hand, indicate poor fit between the model and the data. As a second measure of goodness of fit we used the "Goodness of Fit Index."22 This index reaches a maximum value of 1 when the fit between data and model is perfect; 0.9 is generally considered the threshold for an acceptable model fit.
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Results |
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Fasting lipids and apolipoproteins, postprandial lipemia, and lipoprotein-modifying enzymes in normotriglyceridemic and hypertriglyceridemic men are given in Tables 1
and 2. Age and BMI were similar in both study groups. Cholesterol, non–HDL-C (ie, total cholesterol minus HDL-C), apoB, fasting TGs, and postprandial lipemia were increased and HDL-C, in turn, was decreased in the hypertriglyceridemic group (Table 1). HDL apolipoproteins, apoA-I, and apoA-II, the activity of endothelial lipases in postheparin plasma, and CETP mass and activity did not statistically differ between the groups (Tables 1 and 2).
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Relationship of CETP to Plasma Lipoproteins and Endothelial Lipases in Normotriglyceridemic Men on an Unrestricted Diet
Relationships between fasting TGs, postprandial lipemia (ie, the area under the postprandial TG curve normalized to the fasting TG concentration13 14 ), CETP mass and activity, and endothelial lipases are given in Table 3. Age and BMI were unrelated to any of the above parameters (P>.05). The interrelationships between TGs, postprandial lipemia, and endothelial lipases are consistent with the results of previous investigations: fasting TGs showed a moderately strong, direct relationship to postprandial lipemia;13 LPL showed significant inverse relationships both to postprandial lipemia6 and HL but not to fasting TGs; CETP mass and activity were closely and directly related.18 23 An interesting, novel finding was a tight direct relationship between CETP and LPL activity (Figure, A).
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Subsequently, we evaluated the effects of variation in fasting and postprandial TGs, CETP, and endothelial lipases on the concentration of HDL components in the normotriglyceridemic group (Table 4). As expected, HDL-C and apoA-I were directly related to LPL activity and inversely so to fasting TGs and postprandial lipemia. Plasma CETP showed strong direct associations with apoA-I (Figure
, B) and weaker direct associations with HDL-C (C). After statistical adjustment for the tight direct relationship between LPL and CETP by partial correlation analysis, CETP mass and activity were found to be unrelated to HDL-C and apoA-I (all P>.05).
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Lipoproteins from postabsorptive plasma from 14 normotriglyceridemic men were separated by using zonal ultracentrifugation. The levels, weight percentages of CEs and TGs, and ratios of TGs/CEs, TGs/protein, and CEs/protein of VLDL, IDL, LDL, HDL2, and HDL3 showed no significant relationships to plasma CETP in these subjects (data not shown).
Relationship of CETP to Plasma Lipoproteins and Endothelial Lipases in Hypertriglyceridemic Men on a Hypolipidemic Diet
Relationships between fasting and postprandial TGs, CETP, and endothelial lipases in the men with moderate, primary hypertriglyceridemia are shown in Table 3. Age and BMI were unrelated to any of the parameters above (P>.05), with the exception of an inverse association of age with fasting TGs (r=-.546, P<.01). Fasting TGs were directly related to postprandial lipemia, and CETP mass was directly related to CETP activity. No significant relationships were present between endothelial lipases and either postprandial lipemia or CETP (Figure, A, and Table 3). When the effects of variation in fasting and postprandial TGs, CETP, and lipases on HDL levels were evaluated in the hypertriglyceridemic group, only CETP mass showed a significant, inverse relationship with apoA-I and HDL-C (Figure, B and C, and Table 4).
Comparison of the Association Structures Between HDL and Its Predictor Variables in Hypertriglyceridemic Men on a Hypolipidemic Diet and Normotriglyceridemic Men
Strong interrelationships between independent predictor variables, such as those present in the normotriglyceridemic study group (Table 3), complicated the interpretation of univariate regression analysis. To avoid the problems associated with multicolinearity, we used structural equation modeling, a method that allows the incorporation of the intercorrelations between the predictor variables in the model. In these analyses we used a multiple regression approach, with HDL-C and apoA-I as the dependent variables and TGs, postprandial lipemia, CETP mass, LPL, and HL as the predictor variables. For each of the dependent variables a model was calculated in which the intercorrelations and regression weights were forced to be the same for both the normotriglyceridemic and hypertriglyceridemic groups. This analysis directly tests the hypothesis that the association structure is the same in both groups. Using HDL-C as the dependent variable, the structural equation model comparing the normotriglyceridemic with the hypertriglyceridemic group yielded 220=34.06, P=.026 (goodness-of-fit index=.803), thus indicating that the two groups cannot be modeled using the same regression model.21 22 Using apoA-I as the dependent variable yielded the same result (220=31.89, P=.044; goodness-of-fit index=.794). Similar results were obtained when CETP activity rather than CETP mass was used as one of the predictor variables in models for both HDL-C and apoA-I (both P<.005). Hence, the results of structural equation modeling indicated that the overall regression models for the two groups differ. Subsequently, we evaluated which relationships between individual independent predictor variables, ie, fasting and postprandial TGs and lipoprotein-modifying enzymes, and the outcome, ie, HDL components, were statistically different between both study groups. First, the r values obtained for the respective relationship in each group were subjected to Fisher's transformation to Z.19 The standard normal score calculated by using the transformed values reached significance for the relationships between HDL-C and postprandial lipemia (P<.05), CETP mass (P<.01), and CETP activity (P<.01) and for the relationships between apoA-I and postprandial lipemia, CETP mass and activity (all P<.01), and HL activity (P<.05).20
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Discussion |
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CETP catalyzes the equilibration of neutral core lipids, ie, CEs and TGs, between all lipoprotein particles in plasma.4 In humans, this phenomenon appears to be of quantitative importance since CETP diverts CEs from HDL to TGRLPs in gram quantities per day in exchange for TGs.24 25 26 Complete lack of active CETP in humans homozygous for mutations in the CETP gene,27 in some animal species,4 and after immunologic blockade of CETP in rabbits28 29 leads to a drastic increase in HDL-C. Humans heterozygous for genetic CETP defects and having
50% of normal CETP activity nevertheless exhibit an average 1.7-fold increase of HDL-C.30 Apart from the situation of CETP deficiency due to defects in the CETP gene, however, the inverse relationship between CETP and HDL-C is not readily apparent. Several studies have investigated whether the common fluctuations and/or variations of CETP concentrations in healthy, normolipidemic subjects on unrestricted diets affect their HDL levels.30 31 32 33 34 Only one study32 found the expected inverse relationship between CETP and HDL-C, whereas the others observed either no significant relationship30 31 33 or even a direct one.34 In the present study, we aimed at using very homogeneous study populations by excluding women and subjects with confounding factors like smoking,35 36 obesity,37 38 and endurance exercise.39 In univariate analysis of the normotriglyceridemic group, CETP showed a strong direct association with apoA-I and a somewhat weaker direct association with HDL-C; these findings have also been reported by Marcel et al.34 In addition, CETP was directly related to LPL activity. However, partial correlation analysis, which also took into account the effects of LPL activity, revealed essentially negative results with regard to CETP; there was no relationship between CETP mass and activity and HDL-C, HDL apolipoproteins, HDL subfractions, and HDL composition independent of LPL activity. Which metabolic scenario could plausibly explain these findings? LPL hydrolyzes TGRLPs, thereby providing surface material to be integrated into HDL.3 Enrichment of HDL particles with lipid is known to delay apoA-I catabolism, thereby increasing apoA-I plasma concentrations.40 An augmented pool of apoA-I could provide more binding sites for CETP and, in this way, increase CETP plasma concentrations.34 Our results in normotriglyceridemic men support this concept and extend it to the putative root of the metabolic scenario, ie, LPL. The major finding in our normotriglyceridemic group, however, was the lack of any appreciable independent effect of CETP on HDL levels and HDL composition. Similarly, recent studies41 42 have failed to demonstrate an independent effect of CETP on LDL subfraction concentrations and distribution in predominantly normotriglyceridemic subjects. These results do not, however, necessarily rule out an independent influence of CETP on VLDL subfractions43 or on lipoprotein subpopulations based on apolipoprotein content.44
A major novel approach to reconcile these data with a role for CETP in the metabolic routing of cholesterol and TGs among plasma lipoproteins in humans was undertaken by Mann et al.45 In vitro incubation of native plasma from normotriglyceridemic and hypertriglyceridemic subjects revealed that in normotriglyceridemia net CE transport from HDL to VLDL is determined by VLDL concentration, while in hypertriglyceridemia CETP levels become rate limiting. This hypothesis, based on in vitro findings, is supported by the present in vivo observations; CETP mass was closely inversely related to HDL-C and apoA-I plasma concentrations in nonsmoking, nonobese men with moderate, primary hypertriglyceridemia on a hypolipidemic diet. If these results were to reflect a causal relationship, variation in CETP concentrations could account for 25% of the variability in HDL-C in these patients. CETP activity, however, failed to show significant inverse relations to HDL components in these patients. The reason for this discrepancy could be methodological, as isotopic transfer assays are less sensitive and precise than direct measurement of CETP mass in plasma samples from hypercholesterolemic subjects.4 23
Two studies in 50 and 59 hyperlipidemic subjects failed to show an inverse relationship of CETP and HDL-C.23 Three reasons could account for this discrepancy: the inclusion of women, who have higher CETP and HDL levels than men; the inclusion of a sizable proportion of patients with isolated hypercholesterolemia; and the inclusion of several types of hypertriglyceridemic subjects, such as patients with types III and V hyperlipoproteinemia. Two recent studies support the results of the present investigation in different subgroups of hypertriglyceridemic subjects: Tato et al46 report that CETP activity and HDL-C showed a significant inverse association in 47 patients with combined hyperlipidemia but not in study groups with normolipidemia or isolated hypercholesterolemia. Moulin et al47 also found a significant inverse association between CETP and HDL-C in hypertriglyceridemic patients but not in normotriglyceridemic patients with the nephrotic syndrome.
A cautionary remark regarding the concept that CETP regulates HDL-C levels depending on the TG level appears appropriate. Like previous investigators,30 31 32 33 34 we studied normolipidemic subjects on an unrestricted diet, while the studies in hyperlipidemic patients were performed after allowing for stabilization of lipoprotein levels on a hypolipidemic diet. At present it is unknown what effects, if any, the differences in dietary intake may have had on the relationships discussed above.
We conclude that physiological variation of CETP depresses HDL-C in nonsmoking, nonobese men with moderate, primary hypertriglyceridemia on a hypolipidemic diet but not in healthy, normotriglyceridemic men on an unrestricted diet. Our data support the concept that an interaction of CETP with hypertriglyceridemia lowers HDL levels and extend it from laboratory45 and animal studies48 to humans with high TG and low HDL-C levels.
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Acknowledgments |
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This work was supported by grant HL-27341 from the National Institutes of Health and by grants S-46/06 and S-07106-MED from the Austrian Fonds zur Forderung der wissenschaftlichen Forschung (all to J.R.P.). The expert technical assistance of Gabriele Trobinger, Isa Hauser, and Christa Pfeifhofer is gratefully acknowledged. Goat anti-human HL IgG was a kind gift from Dr Gunilla Bengtsson-Olivecrona, Department of Medical Biochemistry and Biophysics, University of Umea, Sweden. ApoE phenotyping was kindly performed by Dr H.-J. Menzel, Department of Medical Biology and Human Genetics, University of Innsbruck.
Received April 18, 1995;
revision received May 2, 1996;
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References |
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