Donate Help Contact The AHA Sign In Home
American Heart Association
Arteriosclerosis, Thrombosis, and Vascular Biology
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:56-63

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tato, F.
Right arrow Articles by Grundy, S. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tato, F.
Right arrow Articles by Grundy, S. M.
(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:56-63.)
© 1997 American Heart Association, Inc.

Articles

Determinants of Plasma HDL-Cholesterol in Hypertriglyceridemic Patients

Role of Cholesterol-Ester Transfer Protein and Lecithin Cholesteryl Acyl Transferase

Federico Tato; Gloria L. Vega; Scott M. Grundy

The Center for Human Nutrition (F.T., G.L.V., S.M.G.) and the Departments of Clinical Nutrition (G.L.V., S.M.G.), Internal Medicine (S.M.G.), and Biochemistry (S.M.G.) at the University of Texas Southwestern Medical Center at Dallas.

Correspondence to Gloria Lena Vega, PhD, Center for Human Nutrition, 5323 Harry Hines Blvd, Dallas, TX 75235-9052.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Hypertriglyceridemic patients commonly have low levels of HDL cholesterol. Elevated triglycerides per se may be one cause of low HDL levels, but other factors also may be involved. The current study was designed to define the role of cholesterol-ester transfer protein (CETP) in causation of a low HDL cholesterol in hypertriglyceridemic patients; in addition other factors—lecithin cholesterol acyl transferase (LCAT), hepatic triglyceride lipase (HTGL), and lipoprotein lipase (LPL)—were examined. Plasma activities of CETP and LCAT were measured in 137 male patients with moderate hypertriglyceridemia (plasma triglycerides [TGs] 200 to 500 mg/dL and LDL cholesterol <160 mg/dL). Results were compared with those from 50 normolipidemic men of similar age and body habitus. In addition, lipase activities in postheparin plasma were measured in 118 of the subjects with hypertriglyceridemia. The activities of CETP and LCAT were 17% (P<.01) and 7% (P<.05), respectively, higher in the hypertriglyceridemic group than in control subjects. By stepwise regression analysis CETP appeared to contribute 15.2% and LCAT 9.8% to variation in HDL-cholesterol levels. Activities of LPL and HTGL together contributed an additional 14.1% to HDL-cholesterol variation. In contrast, levels of plasma TG accounted for only 5.4% of the variation. There were no differences in relative contributions of these parameters in patients with and those without coronary heart disease. This study indicates that several factors contribute to the variation in HDL-cholesterol levels in hypertriglyceridemic patients, and five factors—CETP, LCAT, HTGL, LPL, and triglyceride levels—account for almost half of this variation.


Key Words: cholesterol-ester transfer protein • low HDL • hypertriglyceridemia • lecithin acyl transferase


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Patients with hypertriglyceridemia frequently have low plasma levels of HDL-cholesterol1 2 3 4 5 6 ; and these low HDL levels may contribute to the increased risk for CHD.7 8 According to data from the Framingham Heart Study,9 an increased risk for CHD in hypertriglyceridemic patients is found mainly among those with low HDL-cholesterol levels. Furthermore, in prospective population studies, multivariate analysis reveals that a significant portion of the increased risk for CHD associated with elevated triglycerides can be attributed to low HDL levels.10 11

The mechanisms underlying a reduction of HDL-cholesterol become of interest because increased risk for CHD among hypertriglyceridemic patients seems limited largely to those with low HDL-cholesterol levels.9 Hypertriglyceridemia per se appears to lower HDL-cholesterol levels,1 2 3 4 5 6 but several other factors that affect HDL-cholesterol concentrations may modify this response.10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Four of these factors are CETP, LCAT, LPL, and HTGL. In the present study, we have examined the extent to which these particular factors are associated with HDL-cholesterol levels in patients with hypertriglyceridemia. If variations in their activities significantly affect HDL levels in hypertriglyceridemic patients, they could in turn have an atherogenic potential.


*    Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Experimental Design
This study was carried out on plasma samples taken from patients attending the lipid clinic of the Veterans Affairs Medical Center, Dallas, Texas. Its primary aim was to determine CETP activities in patients with hypertriglyceridemia and to correlate these activities with HDL-cholesterol levels. Hypertriglyceridemia was defined as plasma total triglycerides in the range of 200 to 500 mg/dL. A total of 137 men met the criteria for hypertriglyceridemia; results on 42 of these patients have been reported previously for postheparin lipase studies19 but not for CETP studies. Patients were excluded if they were being treated for dyslipidemia, were on steroids, or had a history of excessive alcohol intake, diabetes mellitus or other endocrine disorders, renal disease, severe cardiopulmonary disease, or diseases of the gastrointestinal tract or liver.

Fifty normolipidemic men with normal HDL-cholesterol concentrations served as controls for the CETP study. These men also were control subjects for two other recent reports20 21 ; however, the measurements in these control subjects were made simultaneously with those of the present investigation. The criteria for the control subjects were LDL-cholesterol <160 mg/dL, HDL-cholesterol >=40 mg/dL, and triglycerides <200 mg/dL.

The clinical characteristics and lipid profiles of both hypertriglyceridemic patients and control subjects are presented in Table 1Down. Their ages were similar, but BMIs were significantly higher in hypertriglyceridemic patients. The latter also had higher numerical percentages with existing CHD (47% versus 36%), hypertension (52% versus 40%), use of ß-adrenergic blocking agents (ß-blockers) (22% versus 24%), and cigarette smoking (35% versus 24%), but the differences were not statistically significant. The hypertriglyceridemic patients had significantly higher levels of total cholesterol, triglycerides, and non–HDL cholesterol and lower levels of HDL cholesterol. LDL-cholesterol levels were not different between the two groups.


View this table:
[in this window]
[in a new window]
  		Table 1. Demography of Control Subjects and Hypertriglyceridemic Patients

For the study, blood samples were collected after an overnight fast by venipuncture in tubes containing 1 mg/mL of EDTA, 0.005% chloramphenicol, 0.005% gentamicin sulfate, 0.01% NaN3, and 100 IU/mL aprotinin. Aliquots of plasma samples were frozen at -70°C for measurement of CETP and LCAT activities. The stability of CETP at -70°C was previously documented.20 21 The rest of the plasma was used for the measurement of total cholesterol, triglycerides, and lipoprotein cholesterol. These measurements were carried out within 5 days of collection. Activities of LPL and HTGL also were measured in postheparin plasma of 118 of the 137 patients with hypertriglyceridemia.

Measurement of Plasma Lipids and Lipoproteins
Levels of plasma total cholesterol and triglyceride were measured enzymatically.26 27 ApoB-containing lipoproteins were precipitated with 0.55 mmol/L phosphotungstic acid, and 25 mmol/L magnesium chloride28 ; HDL-cholesterol was measured enzymatically in the soluble fraction. LDL-cholesterol was calculated using the Friedewald formula.29 For plasma samples with triglycerides of 300 mg/dL or greater, LDL-cholesterol and HDL-cholesterol levels were measured by the ß-quantification technique,30 and phosphotungstic acid–magnesium chloride was used as the precipitating agent.28

Measurement of CETP Activity
Plasma CETP activities were determined in vitro by a modification of the method of Tollefson and Albers31 ; this procedure was described in detail in a previous report.20 Briefly, CETP activity is expressed as percentage transfer of tritiated cholesteryl esters from HDL3 (donor lipoprotein) to excess, unlabeled LDL (acceptor lipoprotein) in the presence of a small volume of the patient's plasma. Incubations were performed for 16 hours. CETP activities assayed under this condition correlate well with plasma CETP mass.20 All samples were assayed in duplicate. A plasma sample with low CETP activity (<25% transfer) and a plasma sample with high CETP activity (>35% transfer) were included in each assay as quality control. The within assay and between-assay coefficients of variation were <5%. The physiological coefficient of variation was 5.76±2.52%.20

It is important to distinguish between use of the word "activity" as it indicates the mass of CETP and uses of the term to indicate rate of transfer of cholesterol esters in vivo. Some investigators have used it in the latter sense; however, we did not study the latter properties in the present study.

Measurement of LCAT Activity
LCAT activity was measured by a modification of the method described by Chen and Albers.32 Activities of LCAT were measured in all 137 hypertriglyceridemic patients and the 50 control subjects used for CETP measurements. None of the LCAT data have been presented previously. With this technique, LCAT activity likewise correlates with LCAT mass, not with overall esterification rate. According to this procedure, proteoliposomes containing tritiated unesterified cholesterol and apolipoprotein A-I were preincubated with 2% BSA in the presence of assay buffer (10 mmol/L Tris, 150 mmol/L NaCl, 1 mmol/L EDTA, pH 7.4) at 37°C for 30 minutes. LCAT activity was measured in the plasma supernatant after precipitation of apoB-containing lipoproteins with phosphotungstic acid. Precipitation avoided interference of high triglyceride levels with the assay procedure. Four microliters of the supernatant was coincubated for 30 minutes with 250 µL of the proteoliposome mixture in the presence of 25 µL of 43 mmol/L ß-mercaptoethanol at 37°C. The reaction was stopped by adding to each tube 1.0 mL of 0.5% digitonin in 95% ethanol followed by 75 µL of 0.75% cholesterol in 95% ethanol. Samples were mixed vigorously and centrifuged at 5000 rpm for 15 minutes to precipitate the remaining free cholesterol. A 1-mL aliquot of the supernatant was counted for radioactivity for 20 minutes in a liquid scintillation counter. Percentage esterification was derived from the total activity, and the radioactivity was recovered in the ethanol-digitonin supernatant after subtraction of the blank. LCAT activity was subsequently expressed in nanomoles of cholesterol esterified per hour per milliliter of plasma. Values were corrected for the variation of quality controls. In each assay, samples, blanks, and quality controls were run in duplicate. Intra-assay and interassay coefficients of variation were 1.5% and 3.6%, respectively.

The ethanol-digitonin precipitation of free cholesterol was performed as described by Piran and Morin.33 Results obtained with this procedure were compared with results obtained by thin-layer chromatography and recovery of esterified cholesterol in both methods was comparable and averaged near 100% recovery. Moreover, the precipitation of radiolabeled free cholesterol in the current assay averaged 98.0±0.09%.

Postheparin LPL and Hepatic LPL Measurements
LPL and HTGL activities were measured in postheparin plasma as detailed previously.19 Briefly, patients received an intravenous injection of 75 IU of porcine heparin (Elkins-Sinn Inc) per kg of body weight after a 12-hour fast. Blood was drawn into tubes that contained EDTA before and 15 minutes after injection. Plasma samples were frozen at -70°C immediately upon collection and stored for analysis. LPL activity was measured in a small aliquot of plasma in the presence of exogenous apoC-II, after inhibiting HTGL by sodium dodecyl sulfate. HTGL activity was measured in a separate aliquot of plasma after inhibition of LPL by high ionic strength sodium chloride. The assay substrate used to measure the activity of each enzyme consisted of an artificial emulsion containing a mixture of nonradioactive and radioactive triolein stabilized with gum arabic. Samples were incubated at 37°C during the hydrolysis reaction. The hydrolysis was stopped by placing the tubes in ice and extracting the free fatty acids released with organic solvents.19 The release of radioactive free fatty acid by the lipase reactions was quantified, and the enzyme activities are expressed as millimoles per hour per milliliter of plasma.19 The intra-assay and interassay coefficients of variation were <5.0%.

Fifty-one normolipidemic control subjects were compared with current hypertriglyceridemic patients for postheparin lipase activities. The results for these control subjects have been reported previously.19 Clinical characteristics of these control subjects were age, 58±9 years; BMI, 27±4 kg/m2; total cholesterol triglycerides, 139±53 mg/dL; and HDL-cholesterol, 47±6 mg/dL.

Statistical Analysis
The results are summarized as mean±SD. Comparison of means between two groups was made by using two-sample t tests. Comparisons between more than two groups were done by one-way ANOVA followed by Bonferroni-adjusted t tests for multiple comparisons. Differences in the frequency of categorical variables (CHD, hypertension, smoking, intake of ß-blockers) were tested with the {chi}2 test. The distribution of CETP activity was tested for normality using Wilk-Shapiro tests for n <50 and Anderson-Darling tests for n >50. Levene's test was performed to test for homogeneity of variances. Correlations were calculated by linear regression and stepwise regression analysis. A probability value of .05 was considered significant. Data management and statistical analyses were performed using CLINFO (BBN Software Co) and BMDP (SPSS, Inc) software.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 *Results
down arrowDiscussion
 down arrowReferences
 
Activities of CETP and LCAT are presented in Table 2Down for 137 hypertriglyceridemic patients and 50 normolipidemic control subjects. The mean CETP activity was 17% higher in the hypertriglyceridemic group compared with the normolipidemic group (P<.01). By statistical evaluation, the distribution of CETP activities was unimodal in both groups. No evidence of bimodality in CETP distribution was noted. There was no correlation between CETP activities and total cholesterol, LDL-cholesterol, or triglyceride levels. There were no differences in CETP activities between hypertriglyceridemic patients taking and those not taking ß-blockers (P=.93). LCAT activities also were 7% higher in hypertriglyceridemic patients compared with the normolipidemic group (P<.05). The distribution of LCAT activities likewise was unimodal. In the normolipidemic group, CETP and LCAT activities were positively correlated; however, this correlation was not observed in the hypertriglyceridemic group (Fig 1Down).


View this table:
[in this window]
[in a new window]
  		Table 2. Plasma Levels of CETP and LCAT



View larger version (19K):
[in this window]
[in a new window]
  		Figure 1. Comparison of CETP activity (% transfer) and LCAT activity (nanomoles per hour per milliliter) in normolipidemic controls (A) and hypertriglyceridemic patients (B).

Postheparin LPL and HTGL activities were measured in 118 hypertriglyceridemic patients and compared with CETP and LCAT activities in the same patients by a series of statistical analyses. The first analysis compared patients with categorically low HDL levels (HDL-cholesterol <35 mg/dL) with those having higher levels (Table 3Down). Patients with lower HDL levels had triglyceride levels similar to those with higher HDL levels, but the low-HDL patients had significantly higher activities of CETP and HTGL, as well as lower LCAT/CETP and LPL/HTGL ratios.


View this table:
[in this window]
[in a new window]
  		Table 3. Subgroup Analysis of Hypertriglyceridemic Patients

The second analysis provided univariate correlations for hypertriglyceridemic patients between HDL-cholesterol levels and (1) plasma triglyceride concentrations (Fig 2Down), (2) CETP and LCAT activities (Fig 3Down), and (3) LPL and HTGL activities (Fig 4Down). In the triglyceridemic group, the correlation between plasma triglycerides and HDL-cholesterol levels was relatively weak (Fig 2Down), and it was not statistically significant. In contrast, HDL-cholesterol levels were significantly correlated with both CETP and LCAT activities (Fig 3Down). The correlation was negative for CETP and positive for LCAT, and it was stronger for CETP (r2=.152) than for LCAT (r2=.09). As shown in Fig 4Down, LPL activities were positively correlated with HDL-cholesterol levels (r2=.073), and HTGL activities were inversely related (r2=.053). Compared with previously obtained normal values for LPL and HTGL activities,19 mean LPL activities for current hypertriglyceridemic patients were significantly lower, whereas HTGL activities were distinctly elevated (Table 4Down).



View larger version (20K):
[in this window]
[in a new window]
  		Figure 2. Comparison of plasma levels of triglyceride (in milligrams per deciliter) and HDL-cholesterol levels in hypertriglyceridemic patients.



View larger version (20K):
[in this window]
[in a new window]
  		Figure 3. Comparison of HDL-cholesterol levels and CETP (% transfer) (A) and LCAT (nanomoles per hour per milliliter) (B) in patients with hypertriglyceridemia.



View larger version (21K):
[in this window]
[in a new window]
  		Figure 4. Postheparin LPL activity (millimoles per hour per milliliter) (A) and hepatic triglyceride lipase (millimoles per hour per milliliter) (B) compared with HDL-cholesterol levels in hypertriglyceridemic patients.


View this table:
[in this window]
[in a new window]
  		Table 4. Post Heparin LPL and HTGL Activities

The third analysis was a stepwise regression analysis in which categorical variables, lipid and lipoprotein values, and transfer and enzyme activities were entered. Those factors that statistically contributed to HDL variation are listed in Table 5Down. CETP activities were the most highly correlated with HDL-cholesterol variation. Additional significant contributions also were made by LCAT, HTGL, and LPL, and to a lesser extent by triglyceride levels and the use of ß-blockers. These six factors accounted for 47% of the variation in HDL-cholesterol levels in these hypertriglyceridemic patients. Although the contributions of LPL and HTGL activities to the variation in HDL-cholesterol levels were relatively low (Table 5Down), it must be noted that for the group as a whole, LPL and HTGL activities were significantly higher and lower, respectively, than values in control subjects.


View this table:
[in this window]
[in a new window]
  		Table 5. Relative Contribution of Each Independent Variable to HDL-Cholesterol Variation in Hypertriglyceridemic Patients

CETP and LCAT seemingly have opposite effects on HDL-cholesterol levels. The same is true for LPL and HTGL. Furthermore, these two sets of factors may act in concert on lipoprotein metabolism. For this reason, a regression analysis that enters LCAT/CETP and LPL/HTGL ratios could reveal a greater influence of these four factors than determined individually. Therefore, stepwise regression analysis was performed using these ratios. Percentage contributions to HDL-cholesterol variation for LCAT/CETP and LPL/HTGL ratios were 28% (r2=.28) and 13.4% (r2=.134), respectively (Fig 5). Thus, the contributions of ratios approximated the sum of influences of individual components of the ratios; this finding does not prove a molecular interaction of the components (eg, LCAT and CETP), although low ratios are typical of patients with the lowest HDL-cholesterol levels (see Table 3Up).

Finally, since hypertriglyceridemic patients were divided fairly evenly between those with and without CHD, various parameters for the two subgroups were compared (Table 6Down). Patients without CHD were somewhat older, and they had significantly lower postheparin LPL activities; otherwise no differences were noted. Mean CETP activities were not different between the two groups.


View this table:
[in this window]
[in a new window]
  		Table 6. Comparison of Parameters Between Hypertriglyceridemic Patients With and Without Coronary Heart Disease


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
Patients with hypertriglyceridemia commonly have low HDL-cholesterol levels1 2 3 4 5 6 ; and these low levels may increase the risk for CHD.7 8 Furthermore, hypertriglyceridemic patients with low HDL-cholesterol levels are at greater risk for CHD than those with normal levels.9 If the causes of low HDL-cholesterol levels in hypertriglyceridemic patients could be determined, rational therapeutic approaches might be developed. One cause of low HDL in hypertriglyceridemia may be the high triglyceride level itself. Several reports1 2 3 6 10 indicate that triglyceride levels are inversely correlated with HDL-cholesterol concentrations. The mechanisms whereby higher triglyceride concentrations per se lower HDL-cholesterol levels have been studied previously.6 34 35 36 37 38 An increase in plasma triglycerides appears to enhance the transfer of cholesterol esters out of HDL particles and into triglyceride-rich lipoproteins. Presumably an increase in triglyceride levels indicates a greater number of TGRLPs to accept cholesterol esters. This transfer is mediated by CETP; but for a given level of CETP, more cholesterol-ester transfer occurs in the presence of elevated triglycerides.35 This action thus should lower HDL-cholesterol concentrations. However, in the present study, there was little inverse correlation between triglyceride levels and HDL-cholesterol concentrations. Seemingly when triglyceride levels reach the hypertriglyceridemic range, further increases in triglyceride concentrations do not lead to a greater transfer of cholesterol esters from HDL. Thus, the inverse relationship between triglyceride concentrations and HDL-cholesterol levels is relatively strong when triglyceride levels are within the normal range6 ; but according to our present results, further fall in HDL-cholesterol levels apparently ceases once triglyceride concentrations reach a distinctly elevated range. In our patients, all of whom had definite hypertriglyceridemia, factors other than changes in triglyceride levels must have accounted for most of the variation in the HDL-cholesterol levels.

Another potential mechanism for low HDL-cholesterol levels in hypertriglyceridemic patients is a high HTGL activity. Several investigations have shown that a high activity of HTGL is accompanied by low HDL levels39 40 41 42 43 44 45 46 ; this relationship moreover holds in patients with hypertriglyceridemia.19 Furthermore, a previous investigation from our laboratory19 and the expanded databases of the present study indicate that a high frequency of elevated HTGL activities exists in hypertriglyceridemic patients (Table 4Up). The mechanism of this relationship is not clear. Research in rabbits showed that infusion of cholesterol-enriched ß-VLDL increases HTGL activity47 ; but infusion of a triglyceride-rich emulsion has no effect on HTGL expression.47 Thus, it is unknown whether high plasma triglycerides cause elevated HTGL or vice versa. In our hypertriglyceridemic patients, mean HTGL activities appeared to be inversely related to mean HDL-cholesterol levels; those patients with low HDL-cholesterol levels had significantly higher HTGL activities than did the subgroup with higher HDL levels (Table 3Up). Also, for the whole group, HTGL activities were significantly elevated, compared with normolipidemic control subjects (Table 4Up). Thus, high HTGL activities may have contributed importantly to the low mean of HDL-cholesterol level in our hypertriglyceridemic patients. Mechanisms for high HTGL activities are not known; however, a recent study by Cohen et al48 indicates that allelic variation in the HTGL gene correlates significantly with HDL-cholesterol levels, suggesting a link to HTGL gene expression.

Besides increased triglyceride levels and high HTGL activities, which were associated with lower mean HDL-cholesterol levels in hypertriglyceridemic patients, other factors may have contributed to variation in HDL-cholesterol concentrations. Even so, degree of hypertriglyceridemia and the extent of HTGL elevation were not highly correlated with variability of HDL-cholesterol levels in these patients (Table 4Up). The dominant factor correlating with HDL-cholesterol variation among current patients was the activity of CETP. Differences in CETP activities correlated with {approx}15% of the variability in HDL-cholesterol concentrations. In hypertriglyceridemic patients, the mean CETP activity was somewhat higher than that of the control group, but the absolute difference was relatively small and much overlap was noted. Therefore, the generally low HDL-cholesterol levels in hypertriglyceridemic patients cannot be explained by a consistently elevated CETP. On the other hand, variation in CETP activity correlated significantly with HDL-cholesterol concentrations within this group.

Whether CETP activities are a physiological determinant of plasma HDL-cholesterol levels is uncertain. Patients with a genetic deficiency of CETP have markedly elevated HDL-cholesterol concentrations49 50 51 ; this suggests that CETP plays a major role in the transfer of cholesterol esters from HDL to other lipoproteins. Other reports52 53 54 55 56 57 note that various forms of hyperlipidemia often manifest high activities of CETP; patients with these conditions commonly have low HDL-cholesterol levels that might be the result of high CETP activities. In previous studies of CETP activities in hyperlipidemic states,52 53 54 55 56 57 whenever CETP activities are high, total cholesterol levels have been consistently elevated; this is true whether or not hypertriglyceridemia is present. For example, in a study from our laboratory,20 both hypercholesterolemic patients and those with combined hyperlipidemia had elevated CETP activities; thus, some effect mediated by high cholesterol levels apparently induces elevated CETP activities. There is a paucity of literature on CETP activities in hypertriglyceridemic patients who do not have concomitant hypercholesterolemia; the present data revealed a slightly higher level of CETP in hypertriglyceridemic patients, compared with normolipidemic subjects. However, it is uncertain whether elevated triglycerides actually cause small increases in CETP levels as do hypercholesterolemic states. If so, the effect is much less pronounced.

Another recent report from our laboratory21 examined CETP activities in normolipidemic patients with low HDL-cholesterol levels. In this group, mean CETP activities likewise were significantly increased; however, CETP levels were bimodally distributed. A subgroup comprising about 25% of these low-HDL patients had elevated CETP activities. Most patients of this subgroup were devoid of other factors affecting HDL-cholesterol levels, eg, increased HTGL and/or decreased LPL activities. This finding suggested to us that elevated CETP may have been causally related to the low HDL-cholesterol levels in this subgroup. The remainder and majority of low-HDL patients had CETP activities that overlapped those of the control group; moreover, many patients in this subgroup had abnormalities in HTGL or LPL activities that could have been responsible for their low HDL levels. In these patients, plasma CETP activities seemingly played no role in reducing HDL-cholesterol levels.

Current findings contrast with the previous result21 in that hypertriglyceridemic patients did not show a bimodal distribution of CETP activities. Instead there was a range of CETP activities that was unimodally distributed; however, in general, those patients with higher CETP activities had lower HDL-cholesterol levels. This latest finding provides additional support for the concept that high activities of CETP are linked to lower HDL-cholesterol levels in humans. An inverse relationship between CETP activities and HDL-cholesterol levels has now been reported in hypercholesterolemic patients20 25 and in some normolipidemic patients with low HDL-cholesterol concentrations21 ; and it was observed in the present study in patients with hypertriglyceridemia. Factors affecting the variability of plasma CETP levels in humans are not well understood; Bu et al58 reported that allelic variation in the CETP gene is linked to HDL cholesterol levels in humans, although this linkage was not noted by Cohen et al.48

Results of the present study should be compared with the report of Mann et al35 on the mechanisms of plasma cholesterol-ester transfer in patients with hypertriglyceridemia. These researchers showed that hypertriglyceridemic patients have a threefold greater net transfer of cholesterol ester to VLDL compared with normotriglyceridemic subjects. This led to an enhanced accumulation of cholesterol esters in VLDL. Moreover, net cholesterol-ester transfer in hypertriglyceridemic patients correlated with CETP activity. These authors concluded that the VLDL concentration determines the rate of net cholesterol-ester transfer; however, in hypertriglyceridemic patients, CETP activity becomes rate-limiting. Similar results were reported previously by Hopkins and Barter.59 These findings are consistent with the data obtained in the present study. Our results suggest that as plasma CETP levels increase in hypertriglyceridemic subjects, more cholesterol ester is transferred to TGRLP, resulting in a reduction in HDL-cholesterol concentrations.

Another factor that correlated with HDL-cholesterol levels was LCAT activity; this correlation was positive, and variation in LCAT activity accounted for {approx}10% of differences in HDL-cholesterol concentrations. LCAT is required for the generation of cholesterol esters for HDL particles, and in the presence of hypertriglyceridemia, when there is abundant unesterified cholesterol present on TGRLP, the availability of LCAT may be one factor that influences the amount of cholesterol ester carried in HDL particles. Previous data on effects of physiological variation of LCAT activities on HDL-cholesterol levels are not available, but it is possible that variable LCAT activities have a greater influence on HDL-cholesterol levels in hypertriglyceridemic patients than in normolipidemic individuals.57 Since a high LCAT activity may raise HDL-cholesterol levels and a high CETP activity reduces the level, the balance between the two activities could be a determining factor for HDL-cholesterol levels. In normotriglyceridemic patients, there was a positive correlation between CETP and LCAT levels, which may have contributed to the maintenance of normal HDL-cholesterol levels. This correlation did not exist in hypertriglyceridemic patients, which could play a role in keeping HDL-cholesterol levels low (Table 3Up).

Previous investigations have shown that HDL-cholesterol concentrations are positively related to LPL activities.15 17 18 19 The present study is in accord; differences in LPL activities had a significant effect on the variation of HDL-cholesterol levels (Fig 4UpDown). However, this effect was relatively small and less than that of CETP. Nonetheless, LPL activities may have a greater effect on mean HDL-cholesterol levels than on the variation in levels (Table 4Up). Mean postheparin LPL activities were significantly lower in hypertriglyceridemic patients than in the control group. This reduction could produce a generalized lowering of HDL-cholesterol levels. The effects of LPL activity on HDL levels are in the opposite direction to those of HTGL; moreover, the LPL/HTGL ratio has been reported to be strongly correlated with HDL-cholesterol levels.12 15 19 Regression analysis showed that the LPL/HTGL ratio accounted for {approx}13% of the variation in HDL-cholesterol levels in our hypertriglyceridemic patients; this value essentially represents the sum of the independent activities of the two lipases on HDL-cholesterol levels.



View larger version (18K):
[in this window]
[in a new window]
  		Figure 5. Plots of LCAT/CETP ratios (A) and LPL/HTGL ratios (B) vs HDL-cholesterol levels in hypertriglyceridemic patients.

In this study it was observed that patients with definite hypertriglyceridemia have a broad range of HDL-cholesterol levels. As indicated by the Framingham Heart Study,9 levels of HDL-cholesterol are a strong predictor of which hypertriglyceridemic patients will develop CHD. This finding suggests that a low HDL level per se is a risk factor. High concentrations of triglycerides may shift HDL-cholesterol levels to a lower range; and in addition HDL-lowering may be accentuated by the common occurrence of elevated HTGL in hypertriglyceridemic patients (Table 4Up). However, the HDL-cholesterol concentration of a given hypertriglyceridemic patient is strongly dependent on the particular activities of CETP, LCAT, HTGL, and LPL. A particularly strong correlation was found for CETP activities; an association also was uncovered for LCAT activities; and a correlation between both HTGL and LPL activities and HDL-cholesterol concentrations was confirmed. There were no differences observed in relative contributions of these parameters in patients with and without CHD. However, the present investigation suggests a role for CETP and LCAT in regulating HDL-cholesterol levels in hypertriglyceridemic patients, and it confirms a role for HTGL and LPL. Almost half of the variation in HDL-cholesterol levels among current hypertriglyceridemic patients depended on variations among these four factors, with the major one being CETP. It is well known that the risk for CHD varies markedly among patients with hypertriglyceridemia; the activities of these four factors could be important determinants of these differences in risk.


*    Selected Abbreviations and Acronyms
 
BMI = body mass index
CETP = cholesterol-ester transfer protein
CHD = coronary heart disease
HTGL = hepatic triglyceride lipase
LCAT = lecithin cholesterol acyl transferase
LPL = lipoprotein lipase
TGRLP = triglyceride-rich lipoprotein


*    Acknowledgments
 
This work was supported by the Department of Veterans Affairs; National Institutes of Health grants HL-29252, GM2178-27, and MO-IRR00633; and unrestricted grants from Bristol-Myers Squibb, New Brunswick, NJ; Merck & Co Inc, West Point, Pa; Merck, Rahway, NJ; the Southwestern Medical Foundation; and the Moss Heart Foundation, Dallas, Texas. The authors express their appreciation for the excellent technical assistance of Biman Pramanik, Hahn Nguyen Tron, Han Tron, and Long Nguyen. The assistance of Kathleen Gray, RN, Terri Shumway, RN, Regina Stroud, RN, Poonam Bahtia, MD, Sally Seubert, RD, and the clinical staff of the Metabolic Unit of the Veterans Affairs Medical Center in Dallas also is gratefully acknowledged. Beverly Adams-Huet, Program Analyst of the General Clinical Research Center at Parkland Medical Center at Dallas, assisted with data management and analysis.

Received August 3, 1995; revision received May 20, 1996;
*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Schaefer EJ, Levy RI, Anderson DW, Dannu RN, Brewer HB. Plasma triglycerides in regulation of HDL-cholesterol. Lancet. 1978;2:391-393.[Medline] [Order article via Infotrieve]
  2. Davis CE, Gordon D, LaRosa J, Wood PDS, Halperin M. Correlations of plasma high-density lipoprotein cholesterol levels with other plasma lipid and lipoprotein concentrations: the Lipid Research Clinics Program Prevalence Study. Circulation. 1980;62(suppl IV):IV-24-IV-30.
  3. Richards EG, Grundy SM, Cooper K. Influence of plasma triglycerides on lipoprotein patterns in normal subjects and in patients with coronary artery disease. Am J Cardiol. 1989;63:1214-1220.[Medline] [Order article via Infotrieve]
  4. Avogaro P, Ghiselli G, Soldan S, Bittolo Bon G. Relationship of triglycerides and HDL cholesterol in hypertriglyceridemia. Atherosclerosis. 1991;92:79-86.
  5. Nikkila EA, Taskinen M-R, Sane T. Plasma high-density lipoprotein concentration and subfraction distribution in relation to triglyceride metabolism. Am Heart J. 1987;113:543-548.[Medline] [Order article via Infotrieve]
  6. Deckelbaum RJ, Granot E, Oschry Y, Rose L, Eisenberg S. Plasma triglyceride determines structure-composition in low and high density lipoproteins. Arteriosclerosis. 1984;4:225-231.[Abstract/Free Full Text]
  7. Miller NE, Thelle DS, Forde OH, Mjos OD. The Tromso heart-study. High-density lipoprotein and coronary heart disease: a prospective case-control study. Lancet. 1977;1:965-968.[Medline] [Order article via Infotrieve]
  8. Assmann G, Schulte H, Oberwittler W, Hause WH. New aspects in the prediction of coronary artery disease: the Prospective Cardiovascular Munster Study. In: Fidge NH, Nestel PJ, eds. Atherosclerosis VII. Amsterdam, Netherlands: Elsevier Science Publishers; 1986:19-24.
  9. Castelli WP. The triglyceride issue: a view from Framingham. Am Heart J. 1986;112:432-437.[Medline] [Order article via Infotrieve]
  10. Austin M. Plasma triglyceride and coronary heart disease. Arterioscler Thromb. 1991;11:2-14.[Abstract/Free Full Text]
  11. Lechleitner M, Miesenbock G, Patsch JR. HDL cholesterol, triglycerides and coronary heart disease. Curr Opin Lipidol. 1990;1:330-333.
  12. Patsch JR, Prasad S, Gotto AM Jr, Patsch W. High density lipoprotein2: relationship of the plasma levels of this lipoprotein species to its composition, to the magnitude of postprandial lipemia, and to the activities of lipoprotein lipase and hepatic lipase. J Clin Invest. 1987;80:341-347.
  13. Brinton EA, Eisenberg S, Breslow JL. Increased apo A-I and apo A-II fractional catabolic rate in patients with low high density lipoprotein-cholesterol levels with or without hypertriglyceridemia. J Clin Invest. 1991;87:536-544.
  14. Wilson MA, Vega GL, Gylling H, Grundy SM. Persistence of abnormalities in metabolism of apolipoproteins B-100 and A-I after weight reduction in patients with primary hypertriglyceridemia. Arterioscler Thromb. 1992;12:976-984.[Abstract/Free Full Text]
  15. Brinton EA, Eisenberg S, Breslow JL. Human HDL cholesterol levels are determined by apo A-I fractional catabolic rate, which correlates inversely with estimates of HDL particle size: effects of gender, hepatic and lipoprotein lipases, triglyceride and insulin levels, and body fat distribution. Arterioscler Thromb. 1994;14:707-720.[Abstract/Free Full Text]
  16. Montali A, Vega GL, Grundy SM. Concentrations of apolipoprotein A-I–containing particles in patients with hypoalphalipoproteinemia. Arterioscler Thromb. 1994;14:511-517.[Abstract/Free Full Text]
  17. Taskinen MR, Nikkila EA. High density lipoprotein subfractions in relation to lipoprotein lipase activity of tissues in man: evidence for reciprocal regulation of HDL2 and HDL3 levels by lipoprotein lipase. Clin Chim Acta. 1981;112:325-332.[Medline] [Order article via Infotrieve]
  18. Goldberg IJ, Blaner WS, Vanni TM, Moukides M, Ramakrishnan R. Role of lipoprotein lipase in the regulation of high density lipoprotein apolipoprotein metabolism: studies in normal and lipoprotein lipase-inhibited monkeys. J Clin Invest. 1990;86:463-473.
  19. Blades B, Vega GL, Grundy SM. Activities of lipoprotein lipase and hepatic triglyceride lipase in post-heparin plasma of patients with low concentrations of high density lipoprotein cholesterol. Arterioscler Thromb. 1993;13:1227-1235.[Abstract/Free Full Text]
  20. Tato F, Vega GL, Tall A, Grundy SM. Relationship between cholesterol ester transfer protein activities and lipoprotein cholesterol in patients with hypercholesterolemia and combined hyperlipidemia. Arterioscler Thromb Vasc Biol. 1995;15:112-120.[Abstract/Free Full Text]
  21. Tato F, Vega GL, Grundy SM. Bimodal distribution of cholesteryl ester transfer protein activities in normotriglyceridemic men with low HDL cholesterol concentrations. Arterioscler Thromb Vasc Biol. 1995;15:446-451.[Abstract/Free Full Text]
  22. Agellon LB, Walsh A, Hayek T, Moulin P, Jiang XC, Shelanski SA, Breslow JL, Tall AR. Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice. J Biol Chem. 1991;266:10796-10801.[Abstract/Free Full Text]
  23. Walsh A, Ito Y, Breslow JL. High levels of human apolipoprotein A-I transgenic mice result in increased plasma levels of small high density lipoprotein (HDL) particles comparable to human HDL3. J Biol Chem. 1989;264:6488-6494.[Abstract/Free Full Text]
  24. Neary R, Bhatnagar D, Durrington P, Ishola M, Arrol S, Mackness M. An investigation of the role of lecithin:cholesterol acyltransferase and triglyceride-rich lipoproteins in the metabolism of pre-beta high density lipoproteins. Atherosclerosis. 1991;89:35-48.[Medline] [Order article via Infotrieve]
  25. McPherson R, Hogue M, Milne RW, Tall AR, Marcel YL. Plasma cholesteryl ester transfer protein in hyperlipoproteinemia: relation to cholesteryl ester transfer protein activity and other lipoprotein variables. Arterioscler Thromb. 1991;11:797-804.[Abstract/Free Full Text]
  26. Roeschlau P, Bernt E, Gruber W. Enzymatic determination of total cholesterol in serum. Z Klin Chem Klin Biochem. 1974;12:226-227.
  27. McGowan MW, Artis JD, Strandbergh DR, Zack B. A peroxidase coupled method for the colorimetric determination of serum triglycerides. Clin Chem. 1983;29:538-542.[Abstract/Free Full Text]
  28. Assmann G, Schriewer H, Schmitz G, Hagele E-O. Quantification of high-density-lipoprotein cholesterol by precipitation with phosphotungstic acid/MgCl2. Clin Chem. 1983;29:2026-2030.[Abstract/Free Full Text]
  29. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499-502.[Abstract]
  30. Lipid Research Clinics Program. Manual of Laboratory Operations: Lipid and Lipoprotein Analysis. Bethesda, Md: US Government Printing Office; 1984. US Department of Health, Education and Welfare Publication No. NIH F5-628.
  31. Tollefson JH, Albers JJ. Isolation, characterization, and assay of plasma lipid transfer proteins. In: Albers JJ, Segrest JP, eds. Methods of Enzymology. New York, NY: Academic Press Inc; 1994:797-812.
  32. Chen C, Albers JJ. Characterization of proteoliposome containing apolipoprotein A-I: a new substrate for the measurement of lecithin:cholesterol acyltransferase activity. J Lipid Res. 1982;23:680-691.[Abstract]
  33. Piran U, Morin RJ. A rapid radioassay procedure for plasma lecithin-cholesterol acyltransferase. J Lipid Res. 1979;20:1040-1043.[Abstract]
  34. Dullaart RPF, Groener JEM, Erkelens DW. Effect of the composition of very low density lipoproteins on the rate of cholesterylester transfer from high density lipoproteins in man, studied in vitro. Eur J Clin Invest. 1987;17:241-248.[Medline] [Order article via Infotrieve]
  35. Mann JC, Yen FT, Grant AM, Bihain BE. Mechanisms of plasma cholesteryl ester transfer in hypertriglyceridemia. J Clin Invest. 1991;88:2059-2066.
  36. Eisenberg S. Preferential enrichment of large-sized very low density lipoprotein populations with transferred cholesterol esters. J Lipid Res. 1985;26:487-494.[Abstract]
  37. Tall A, Sammett D, Granot E. Mechanisms of enhanced cholesteryl ester transfer from high density lipoproteins to apolipoprotein B-containing lipoproteins during alimentary lipemia. J Clin Invest. 1986;77:1163-1172.
  38. Hayek T, Azrolan N, Verdey RB, Walsh A, Chajek-Shaul T, Agellon LB, Tall AR, Breslow JL. Hypertriglyceridemia and cholesteryl ester transfer protein interact to dramatically alter high density lipoprotein levels, particle sizes, and metabolism. J Clin Invest. 1993;92:1143-1152.
  39. Newmann HH, Barter PJ. Synergistic effects of lipid transfers and hepatic lipase activity promote shedding of apo A-I from HDL and subsequent formation of discoidal HDL. Biochim Biophys Acta. 1990;1044:57-64.[Medline] [Order article via Infotrieve]
  40. Fan J, Wang J, Bensadoun A, Lauer SJ, Dang Q, Mahley RW, Taylor JM. Overexpression of hepatic lipase in transgenic rabbits leads to a marked reduction of plasma high density lipoproteins and intermediate density lipoproteins. Proc Natl Acad Sci U S A. 1994;91:8724-8728.[Abstract/Free Full Text]
  41. Kuusi T, Ehnholm C, Viikari J, Harkonen R, Vartiainen E, Pekka P, Taskinene M-R. Postheparin plasma lipoprotein and hepatic lipase are determinants of hypo- and hyperalphalipoproteinemia. J Lipid Res. 1989;30:1117-1126.[Abstract]
  42. Kuusi T, Saarinen P, Nikkila EA. Evidence for the role of hepatic endothelial lipase in the metabolism of plasma high density lipoprotein2 in man. Atherosclerosis. 1980;36:589-593.[Medline] [Order article via Infotrieve]
  43. Depres J-P, Ferland M, Moorjani S, Nadeau A, Tremblay A, Lupien PJ, Theriault G, Bouchard C. Role of hepatic lipase activity in the association between intra-abdominal fat and plasma HDL-cholesterol in obese women. Arteriosclerosis. 1989;9:485-492.[Abstract/Free Full Text]
  44. Tikkanen MJ, Nikkila EA, Kuusi T, Sipinen S. Reduction of plasma high density lipoprotein2 cholesterol and increase of post-heparin plasma hepatic lipase during progestin treatment. Clin Chim Acta. 1982;115:63-71.
  45. Tikkanen MJ, Nikkila EA, Kuusi T, Sipinen S. High density lipoprotein2 and hepatic lipase: reciprocal changes produced by estrogen and norgestrel. J Clin Endocrinol Metab. 1982;54:1113-1117.[Abstract]
  46. Tikkanen MJ, Nikkila EA. Regulation of hepatic lipase and serum lipoproteins by sex steroids. Am Heart J. 1987;113:562-567.[Medline] [Order article via Infotrieve]
  47. Elbert DL, Warren RJ, Barter PJ, Mitchell A. Infusion of atherogenic lipoprotein particles increases hepatic lipase activity in the rabbit. J Lipid Res. 1993;34:89-94.[Abstract]
  48. Cohen JC, Wang Z, Grundy SM, Stoesz MR, Guerra R. Variation in hepatic lipase and apolipoprotein AI/CIII/AIV loci is a major cause of genetically determined variation of plasma HDL cholesterol levels. J Clin Invest. 1994;94:2377-2384.
  49. Koizumi J, Mabuchi H, Yoshimura A, Michishit I, Takeda M, Itoh H, Sakai Y, Sakai T, Ueda K, Takeda R. Deficiency of serum cholesteryl ester transfer activity in patients with familial hyperalphalipoproteinemia. Atherosclerosis. 1985;90:189-196.
  50. Inazu A, Brown ML, Hesler CB, Agellon LB, Koizumi J, Takata K, Maruhama Y, Mabuchi H, Tall AR. Increased high density lipoprotein caused by a common cholesteryl ester transfer protein gene mutation. N Engl J Med. 1990;323:1234-1238.[Abstract]
  51. Kiozumi J, Inazu Y, Ichiro K, Uno Y, Kajinami K, Miyamoto S, Moulin P, Tall AR, Mabuchi H, et al. Serum lipoprotein lipid concentrations and composition in homozygous and heterozygous patients with cholesteryl ester transfer protein deficiency. Atherosclerosis. 1991;90:189-196.[Medline] [Order article via Infotrieve]
  52. Bagdade JD, Ritter MC, Subbiah PV. Accelerated cholesteryl ester transfer in plasma of patients with hypercholesterolemia. J Clin Invest. 1991;87:1259-1265.
  53. Marcel YL, Tall AR, Hogue M, Milne RW, McPherson R. Plasma lipoprotein phenotypes in response to cholesteryl ester transfer protein levels in dyslipoproteinemia. Adv Exp Med Biol. 1991;285:77-80.[Medline] [Order article via Infotrieve]
  54. Inazu A, Koizumi J, Mabuchi H, Kajinami K, Takeda R. Enhanced cholesteryl ester transfer protein activities and abnormalities of high density lipoproteins in familial hypercholesterolemia. Horm Metab Res. 1992;24:284-288.[Medline] [Order article via Infotrieve]
  55. Tall AR, Granot E, Brocia R, Tabas I, Hesler C, Wiliams K, Denke MA. Accelerated transfer of cholesteryl esters in dyslipidemic plasma: role of cholesteryl ester transfer protein. J Clin Invest. 1987;79:1217-1225.
  56. Moulin P, Appel GB, Gingsberg HN, Tall R. Increased concentration of plasma cholesteryl ester transfer protein in nephrotic syndrome: role in dyslipidemia. J Lipid Res. 1992;33:1817-1822.[Abstract]
  57. Dullaart RFP, Gansevoort RT, Dikkischei BD, De Zeeuw D, De Jong PE, van Tol A. Role of elevated lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein activities in abnormal lipoproteins from proteinuric patients. Kidney Int. 1993;44:91-97.[Medline] [Order article via Infotrieve]
  58. Bu X, Warden CH, Xia YR, De Meester C, Puppione DL, Teruya S, Lokensgard B, Daneshmand S, Brown J, Gray RJ, et al. Linkage analysis of the genetic determinants of high density lipoprotein concentrations and composition: evidence for involvement of the apolipoprotein A-II and cholesteryl ester transfer protein loci. Hum Genet. 1994;93:639-648.[Medline] [Order article via Infotrieve]
  59. Hopkins GJ, Barter PJ. An effect of very low density lipoproteins on the rate of cholesterol esterification in human plasma. Biochim Biophys Acta. 1982;712:152-160.[Medline] [Order article via Infotrieve]



This article has been cited by other articles:


Home page
 Eur Heart JHome page
S. E. Borggreve, H. L. Hillege, G. M. Dallinga-Thie, P. E. de Jong, B. H.R. Wolffenbuttel, D. E. Grobbee, A. van Tol, R. P.F. Dullaart, and on behalf of the PREVEND Study Group
High plasma cholesteryl ester transfer protein levels may favour reduced incidence of cardiovascular events in men with low triglycerides
Eur. Heart J., April 4, 2007; (2007) ehm062v1.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
S. Rashid, B. W. Patterson, and G. F. Lewis
Thematic review series: Patient-Oriented Research. What have we learned about HDL metabolism from kinetics studies in humans?
J. Lipid Res., August 1, 2006; 47(8): 1631 - 1642.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
R. de Vries, F. G. Perton, G. M. Dallinga-Thie, A. M. van Roon, B. H.R. Wolffenbuttel, A. van Tol, and R. P.F. Dullaart
Plasma Cholesteryl Ester Transfer Is a Determinant of Intima-Media Thickness in Type 2 Diabetic and Nondiabetic Subjects: Role of CETP and Triglycerides
Diabetes, December 1, 2005; 54(12): 3554 - 3559.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
J. Q. Zhang, B. Smith, M. M. Langdon, H. L. Messimer, G. Y. Sun, R. H. Cox, M. James-Kracke, and T. R. Thomas
Changes in LPLa and reverse cholesterol transport variables during 24-h postexercise period
Am J Physiol Endocrinol Metab, August 1, 2002; 283(2): E267 - E274.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
S. Barlage, D. Fröhlich, A. Böttcher, M. Jauhiainen, H. P. Müller, F. Noetzel, G. Rothe, C. Schütt, R. P. Linke, K. J. Lackner, et al.
ApoE-containing high density lipoproteins and phospholipid transfer protein activity increase in patients with a systemic inflammatory response
J. Lipid Res., February 1, 2001; 42(2): 281 - 290.
[Abstract] [Full Text]

Home page
 ANN INTERN MEDHome page
K. J. Harjai
Potential New Cardiovascular Risk Factors: Left Ventricular Hypertrophy, Homocysteine, Lipoprotein(a), Triglycerides, Oxidative Stress, and Fibrinogen
Ann Intern Med, September 7, 1999; 131(5): 376 - 386.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
T. P. Bersot, G. L. Vega, S. M. Grundy, K. E. Palaoglu, P. Atagündüz, S. Özbayrakçi, O. Gökdemir, and R. W. Mahley
Elevated hepatic lipase activity and low levels of high density lipoprotein in a normotriglyceridemic, nonobese Turkish population
J. Lipid Res., March 1, 1999; 40(3): 432 - 438.
[Abstract] [Full Text]

Home page
 J. Lipid Res.Home page
C. Bruce, D. S. Sharp, and A. R. Tall
Relationship of HDL and coronary heart disease to a common amino acid polymorphism in the cholesteryl ester transfer protein in men with and without hypertriglyceridemia
J. Lipid Res., May 1, 1998; 39(5): 1071 - 1078.
[Abstract] [Full Text]

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow