High Cholesteryl Ester Transfer Protein Activity Research Articles

Hibernating brown bears are protected against atherogenic dyslipidemia

To investigate mechanisms by which hibernators avoid atherogenic hyperlipidemia during hibernation, we assessed lipoprotein and cholesterol metabolisms of free-ranging Scandinavian brown bears (Ursus arctos). In winter- and summer-captured bears, we measured lipoprotein sizes and sub-classes, triglyceride-related plasma-enzyme activities, and muscle lipid composition along with plasma-levels of antioxidant capacities and inflammatory markers. Although hibernating bears increased nearly all lipid levels, a 36%-higher cholesteryl-ester transfer-protein activity allowed to stabilize lipid composition of high-density lipoproteins (HDL). Levels of inflammatory metabolites, i.e., 7-ketocholesterol and 11ß-prostaglandin F2α, declined in winter and correlated inversely with cardioprotective HDL2b-proportions and HDL-sizes that increased during hibernation. Lower muscle-cholesterol concentrations and lecithin-cholesterol acyltransferase activity in winter suggest that hibernating bears tightly controlled peripheral-cholesterol synthesis and/or release. Finally, greater plasma-antioxidant capacities prevented excessive lipid-specific oxidative damages in plasma and muscles of hibernating bears. Hence, the brown bear manages large lipid fluxes during hibernation, without developing adverse atherogenic effects that occur in humans and non-hibernators.

Elevated CETP activity during acute phase of myocardial infarction is independently associated with endothelial dysfunction and adverse clinical outcome

Objective: Recent data suggests that cholesteryl ester transfer protein (CETP) activity may interact with acute stress conditions via inflammatory-oxidative response and thrombogenesis. We investigated this assumption in patients with ST-elevation myocardial infarction (STEMI). Methods: Consecutive patients with STEMI (n = 116) were enrolled <24-h of symptoms onset and were followed for 180 days. Plasma levels of C-reactive protein (CRP), interleukin-2 (IL-2), tumor necrosis factor (TNFα), 8-isoprostane, nitric oxide (NOx) and CETP activity were measured at enrollment (D1) and at fifth day (D5). Flow-mediated dilation (FMD) was assessed by ultrasound and coronary thrombus burden (CTB) was evaluated by angiography. Results: Neither baseline nor the change of CETP activity from D1 to D5 was associated with CRP, IL-2, TNFα, 8-isoprostane levels or CTB. The rise in NOx from D1 to D5 was inferior [3.5(−1; 10) vs. 5.5(−1; 12); p < 0.001] and FMD was lower [5.9(5.5) vs. 9.6(6.6); p = 0.047] in patients with baseline CETP activity above the median value than in their counterparts. Oxidized HDL was measured by thiobarbituric acid reactive substances (TBARS) in isolated HDL particles and increased from D1 to D5, and remaining elevated at D30. The change in TBARS content in HDL was associated with CETP activity (r = 0.72; p = 0.014) and FMD (r = −0.61; p = 0.046). High CETP activity at admission was associated with the incidence of sudden death and recurrent MI at 30 days (OR 12.8; 95% CI 1.25–132; p = 0.032) and 180 days (OR 3.3; 95% CI 1.03–10.7; p = 0.044). Conclusions: An enhanced CETP activity during acute phase of STEMI is independently associated with endothelial dysfunction and adverse clinical outcome.

CETP inhibitors and cardiovascular disease: Time to think again

Inhibition of cholesteryl ester transfer protein (CETP) lowers plasma low-density lipoprotein cholesterol concentration and raises high-density lipoprotein (HDL) cholesterol, suggesting it might prevent cardiovascular disease (CVD). From the outset, however, the concept has been controversial owing to uncertainty about its effects on HDL function and reverse cholesterol transport (RCT). Although there has long been good evidence that CETP inhibition reduces atherosclerosis in rabbits, the first information on CETP as a CVD risk factor in a prospectively followed cohort was not published until after the first Phase 3 trial of a CETP inhibitor had begun. The worrying finding that CVD incidence was related inversely to plasma CETP has since been reproduced in each of five further prospective cohort studies. Similar results were obtained in subjects on or off statin therapy, for first and second CVD events, and for mortality as well as CVD morbidity. Additionally, two recent studies have found alleles of the CETP gene that lower hepatic CETP secretion to be associated with an increased risk of myocardial infarction. Meanwhile, CETP gene transfer in mice was found to increase RCT from peripheral macrophages in vivo, and human plasma with high CETP activity was shown to have a greater capacity to remove cholesterol from cultured cells than plasma with low activity. This mounting evidence for a protective function of CETP has been given remarkably little attention, and indeed was not mentioned in several recent reviews. It appears to show that CETP inhibition does not test the HDL hypothesis as originally hoped, and raises a pressing ethical issue regarding two Phase 3 trials of inhibitors, involving more than forty thousand subjects, which are currently in progress. As the weight of evidence now clearly supports an adverse effect of CETP inhibition on CVD, an urgent review is needed to determine if these trials should be discontinued.

CETP inhibitors and cardiovascular disease: Time to think again

Inhibition of cholesteryl ester transfer protein (CETP) lowers plasma low-density lipoprotein cholesterol concentration and raises high-density lipoprotein (HDL) cholesterol, suggesting it might prevent cardiovascular disease (CVD). From the outset, however, the concept has been controversial owing to uncertainty about its effects on HDL function and reverse cholesterol transport (RCT). Although there has long been good evidence that CETP inhibition reduces atherosclerosis in rabbits, the first information on CETP as a CVD risk factor in a prospectively followed cohort was not published until after the first Phase 3 trial of a CETP inhibitor had begun. The worrying finding that CVD incidence was related inversely to plasma CETP has since been reproduced in each of five further prospective cohort studies. Similar results were obtained in subjects on or off statin therapy, for first and second CVD events, and for mortality as well as CVD morbidity. Additionally, two recent studies have found alleles of the CETP gene that lower hepatic CETP secretion to be associated with an increased risk of myocardial infarction. Meanwhile, CETP gene transfer in mice was found to increase RCT from peripheral macrophages in vivo , and human plasma with high CETP activity was shown to have a greater capacity to remove cholesterol from cultured cells than plasma with low activity. This mounting evidence for a protective function of CETP has been given remarkably little attention, and indeed was not mentioned in several recent reviews. &nbsp;It appears to show that CETP inhibition does not test the HDL hypothesis as originally hoped, and raises a pressing ethical issue regarding two Phase 3 trials of inhibitors, involving more than forty thousand subjects, which are currently in progress. As the weight of evidence now clearly supports an adverse effect of CETP inhibition on CVD, an urgent review is needed to determine if these trials should be discontinued.

CETP inhibitors and cardiovascular disease: Time to think again.

Inhibition of cholesteryl ester transfer protein (CETP) lowers plasma low-density lipoprotein cholesterol concentration and raises high-density lipoprotein (HDL) cholesterol, suggesting it might prevent cardiovascular disease (CVD). From the outset, however, the concept has been controversial owing to uncertainty about its effects on HDL function and reverse cholesterol transport (RCT). Although there has long been good evidence that CETP inhibition reduces atherosclerosis in rabbits, the first information on CETP as a CVD risk factor in a prospectively followed cohort was not published until after the first Phase 3 trial of a CETP inhibitor had begun. The worrying finding that CVD incidence was related inversely to plasma CETP has since been reproduced in each of five further prospective cohort studies. Similar results were obtained in subjects on or off statin therapy, for first and second CVD events, and for mortality as well as CVD morbidity. Additionally, two recent studies have found alleles of the CETP gene that lower hepatic CETP secretion to be associated with an increased risk of myocardial infarction. Meanwhile, CETP gene transfer in mice was found to increase RCT from peripheral macrophages in vivo, and human plasma with high CETP activity was shown to have a greater capacity to remove cholesterol from cultured cells than plasma with low activity. This mounting evidence for a protective function of CETP has been given remarkably little attention, and indeed was not mentioned in several recent reviews. It appears to show that CETP inhibition does not test the HDL hypothesis as originally hoped, and raises a pressing ethical issue regarding two Phase 3 trials of inhibitors, involving more than forty thousand subjects, which are currently in progress. As the weight of evidence now clearly supports an adverse effect of CETP inhibition on CVD, an urgent review is needed to determine if these trials should be discontinued.

PS13 - 7. Plasma cholesteryl ester transfer protein: a biomarker for hepatic macrophages

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from HDL to LDL and high CETP activity results in an atherogenic lipid phenotype. Thus, inhibiting CETP is a target for dyslipidemia treatment. However, the true origin of CETP in humans is uncertain. We aimed to elucidate the cellular origin of CETP and the relative contribution of adipose tissue and liver to plasma CETP levels.

High cholesteryl ester transfer protein (CETP) activity in acute phase of myocardial infarction predicts short-term mortality by inducing endothelial dysfunction and reduced microvascular perfusion

Background: Recently, much effort has been centered on the development of cholesteryl ester transfer protein (CETP) inhibitors, based on CETP proatherogenic role. However, some evidence indicates exacerbated CETP activity (CETPa) may also favor arterial thrombogenicity and impair endothelial function. In this context, we investigated the relation between CETPa and: 1) endothelial dysfunction; 2) coronary blood flow/myocardial perfusion after reperfusion therapy in patients with ST-elevation myocardial infarction (STEMI). Methods: Consecutive thrombolytic-treated STEMI patients (n=116) were followed prospectively. Plasma C-reactive protein (CRP), IL-2, TNFα, 8-isoprostane, nitric oxide (NOx) levels and CETPa (%) were measured in the first 24 hours (D1) and at 5th day (D5) after MI onset. Culprit artery percutaneous coronary angioplasty (PCA) was performed at a mean 6 days after MI, when pre- and post-procedure myocardial blush grade (MBG) and TIMI flow were measured. At D30 we measured brachial artery flow-mediated dilation (FMD) by ultrasonography. In addition, all patients were genotyped for eNOS polymorphism rs1799983 (G/T). Results: Although admission CETPa had no relation with the change between D1 and D5 in CRP, IL-2, TNFα or 8-isoprostane plasma levels, patients with higher CETPa presented both poor coronary flow (TIMI flow<3, adjusted OR of 22.1 95% CI 2.7–180; p=0.004) and myocardial perfusion (MBG<3, OR 20.4 CI 1.8–101; p=0.001), compared to those with lower CETP activity. Logistic regressions showed admission plasma CETPa higher than median as an independent predictor of cardiac death and new MI in 30 days (OR=12.8, CI 1.25–132, p=0.032), as well as endothelial dysfunction (OR=3.08, CI 1.01–9.37,p=0.048). Consistently, the rise in NOx levels between D1 and D5 was less intense in patients with exacerbated CETPa (5.5 (-1; 12) vs 3.5 (-1; 10); p<0.001). In addition, in order to evaluate if eNOS activity would be critical for the association between CETP and endothelial dysfunction, we observed that only in the presence of the functional eNOS T allele polymorphism the correlation between CETP and FMD was maintained (R2=-0.4, p=0.002). T allele patients with admission CETPa lower than median also presented FMD of 12.2±4 vs 6.0±3mm in those with high CETPa (p=0.040). Conclusions: This is the first study to suggest a relation between high plasma CETP activity in acute STEMI and increased clinical outcomes at 30 days. Our study also indicates a positive association between exacerbated CETP activity in MI and both endothelial dysfunction and poor reperfusion quality post-angioplasty.

GH levels and insulin sensitivity are differently associated with biomarkers of cardiovascular disease in active acromegaly

Acromegaly is characterized by GH excess and insulin resistance. It is not known which of these disorders is responsible for the increased atherogenic risk in these patients. To analyse the associations of GH and homoeostasis model assessment (HOMA) with biomarkers of cardiovascular disease and to compare the above-mentioned variables between patients with active acromegaly and controls. This open cross-sectional study was conducted at a University Hospital. Twenty-two outpatients were compared with sex- and age-matched control subjects. Included clinical features, hormonal status, markers of insulin resistance, lipoprotein profile and biomarkers of cardiovascular disease. Patients presented higher triglyceride (median [IQR]) (1·2[1·1-1·6] vs 0·9[0·6-1·1] mm, P < 0·05), low-density lipoprotein-cholesterol (LDL-C) (mean ± SD) (3·5 ± 0·9 vs 3·0 ± 0·7mm, P < 0·05), apoB (0·98 ± 0·23 vs 0·77 ± 0·22 g/l, P < 0·05), free fatty acid (0·69 ± 0·2 vs 0·54 ± 0·2 mM, P < 0·05), oxidized-LDL (120 ± 22 vs 85 ± 19 U/l, P < 0·05) and endothelin-1 (0·90 ± 0·23 vs 0·72 ± 0·17 ng/l, P < 0·05) levels, increased cholesteryl ester transfer protein (CETP) activity (179 ± 27 vs 138 ± 30%/ml/h, P < 0·01) and lower C reactive protein (CRP) (0·25[0·1-0·9] vs 0·85[0·4-1·4] mg/l; P < 0·05) levels than control subjects. Vascular cell adhesion molecule (VCAM-1) concentration was not different. By multiple linear regression analyses, HOMA explained the variability of triglycerides (25%), high-density lipoprotein-cholesterol (HDL-C) (30%) and CETP activity (28%), while GH independently predicted LDL-C (18%), oxidized-LDL (40%) and endothelin-1 levels (19%). In patients with active acromegaly, GH excess contributes to the development of insulin resistance, and the interaction between both disturbances would be responsible for the appearance of atherogenic pro-oxidative and pro-inflammatory factors. Insulin resistance would be preferably associated with an atherogenic lipoprotein profile and to high CETP activity, while high GH levels would independently predict the increase in LDL-C, ox-LDL and endothelin-1.

Elevated CETP Activity Improves Plasma Cholesterol Efflux Capacity From Human Macrophages in Women

We aim to identify the impact of endogenous cholesteryl ester transfer protein (CETP) activity on plasma capacity to mediate free cholesterol efflux from human macrophages. Endogenous plasma CETP activity was measured in a population of 348 women. We defined a low CETP group corresponding to subjects displaying an endogenous plasma CETP activity within the first tertile and a high CETP group corresponding to subjects with an endogenous plasma CETP activity within the third tertile. Subjects from the high CETP activity group displayed a significant increase in the capacity of their plasma (+8.2%; P=0.001) to mediate cholesterol efflux from human acute monocytic leukemia cell line human macrophages and from ATP-binding cassette transporter A1-dependent pathway (+23.4%; P=0.0001) as compared with those from the low CETP activity group. Multivariate analyses revealed that the impact of CETP activity was independent of plasma lipids levels. Pre-β1-high-density lipoprotein concentrations were significantly elevated (+29.6%; P=0.01) in the high CETP activity group as compared with the low CETP activity group. A positive correlation between pre-β1-high-density lipoprotein levels and plasma efflux efficiency from human acute monocytic leukemia cell line human macrophages was observed (r=0.29, P=0.02). CETP leading to the improvement of plasma efflux capacity, as a result of efficient pre-β-high-density lipoprotein formation and ATP-binding cassette transporter A1 efflux, should be preserved to prevent lipid accumulation in human macrophages.

HOMA-IR and non-HDL-C as predictors of high cholesteryl ester transfer protein activity in patients at risk for type 2 diabetes

Metabolic syndrome (MS) and type 2 diabetes are highly associated with an abnormal lipoprotein profile, which may be generated and accentuated by high cholesteryl ester transfer protein (CETP) activity. Given the difficulty in measuring CETP activity, the aim was to identify simple biochemical predictors of high CETP activity. Eighty five subjects at risk for type 2 diabetes were classified according to the presence of MS. Lipoprotein profile, HOMA-IR and endogenous CETP activity were evaluated. As expected, MS patients presented higher concentration of glucose, insulin, triglycerides and non-HDL-C and lower HDL-C levels. Moreover, MS patients exhibited increased HOMA-IR and CETP activity. Employing a ROC curve for MS, high CETP activity was defined as >250%ml⁻¹ h⁻¹. The predictive variables of high CETP were non-HDL-C≥160mg/dl (OR=11.1;95%IC=3.3-38.2;p<0.001) and HOMA-IR>2.1 (OR=4.4;95%IC=1.3-14.8;p<0.05). High non-HDL-C and insulin resistance were predictors for increased CETP activity which measurement is not accessible for clinical laboratories.

Abstract 18369: Cholesteryl Ester Transfer Protein Activity is Associated with Oxidative Stress Markers During Acute Phase of Myocardial Infarction

Cholesteryl ester transfer protein (CETP) action enriches HDL particles with triglycerides, depletes HDL by cholesterol esters, consequently reducing size of HDL and increasing catabolism of apolipoprotein AI (Apo AI). The HDL phenotype induced by enhanced CETP activity is considered pro-atherogenic. But recent findings have linked increased CETP activity in sepsis-related acute stress to reduced inflammatory response and there is no information regarding CETP activity impact in acute coronary syndromes (ACS). We evaluated the association between CETP activity and oxidative stress and inflammatory response in patients with myocardial infaction (MI). Consecutive patients (n=38) with ST-elevation MI (STEMI) were selected from the Brasilia Heart Study for this investigation. Plasma CETP activity, HDL cholesterol, triglycerides, C-reactive protein (CRP), interleukin-2 (IL2), interleukin-10 (IL10), tumor necrosis factor α (TNFα) and isoprostane (iso-PGF 2α ) levels were measured in the first 24 hours and at the fifth day after MI onset. Patients were divided in two groups, according to CETP median (6 nmol/mL/h) at admission: M1 (CETP activity ≤ median) and M2 (CETP activity &gt; median). On admission, no difference was found between the groups in plasma HDLc (p=0.5), triglycerides (p=0.1), CRP (p=0.5), IL2 (p=0.9), IL10 (p=0.6), TNFα (p=0.2) and isoprostane (p=0.7) levels. On fifth day, both groups experienced similar reductions in CETP activity [M1: -38%(-100;30); M2: -43% (-75;8); p=0.303]. On an analysis of the change between admission and fifth day, there was a major increase in triglycerides (p&lt;0.01) in M2 group [11% (-18;32)] against M1 [3.3% (-49;16)], and also a major increase in isoprostane (p&lt;0.01) in M2 [9.1% (-30;74)] versus M1 [5.7% (-20;37)]. However, there was no significant change in HDLc (p=0.2), CRP (p=0.5), TNFα (p=0.2), IL2 (p=0.1), IL10 (p=0.9) levels between M1 and M2 groups. This is the first study that observed a marked reduction in CETP activity following STEMI. And also, the findings indicate that higher CETP activity at admission is associated with increased triglycerides and isoprostane, a marker of oxidative stress. Such information contributes for the understanding of CETP role during acute phase of ACS.

Impact of Unhealthy Lifestyle Behaviors and Obesity on Cholesteryl Ester Transfer Protein Among Adolescent Males

Cholesteryl ester transfer protein (CETP) has been proposed to be associated with high risk of cardiovascular disease. Increased CETP activity was previously reported in obese adults, although its association with lifestyle behaviors has not been assessed in healthy adolescents. We undertook this study to determine the association between CETP activity and overweight/obesity, insulin resistance markers, components of the metabolic syndrome and lifestyle behaviors in healthy adolescent males. Data were collected from 164 adolescents from an amateur rugby club. Body mass index (BMI), blood pressure (BP), Tanner stages, lipids, glucose, insulin and CETP activity were measured. Questionnaires for daily intake of breakfast, sweet drinks, milk, and hours of TV watching were completed. About 26% of the adolescents were obese and 23% overweight. The prevalence of metabolic syndrome was 6.7%. CETP activity was higher in obese than in normal andoverweight adolescents (174 ± 35, 141 ± 30, and 149 ± 38%/ml/min, respectively; p <0.001). Univariate correlations showed an inverse association between CETP and HDL-C (r = -0.43; p = 0.018) and positive ones with BMI (r = 0.38; p = 0.007), systolic BP (r = 0.20; p <0.01) triglycerides (r = 0.40; p = 0.001), LDL-C (r = 0.46; p <0.001), TV watching >2 h/day (r = 0.17; p 0.02), and milk intake >3 glasses/day (r = 0.16; p = 0.03). Multivariate analysis showed that triglycerides, LDL-C, HDL-C, TV watching >2 h/day, milk intake >3 glasses/day and BMI were significant independent predictors for CETP (R(2) = 0.41). Unhealthy lifestyle habits such as TV watching >2 h daily and milk intake higher than three glasses per day and the increase in BMI were shown to be closely associated with high CETP activity in apparently healthy adolescent males. Future longitudinal studies should be performed to confirm these findings.

Cholesteryl ester transfer protein activity and cardiovascular events in patients with chronic kidney disease stage V

Patients with chronic kidney disease (CKD) have an increased risk for cardiovascular events (CVE). Uraemic dyslipidaemia, which is characterized by low HDL-cholesterol (HDL-C) and elevated triglycerides' levels, may contribute to this elevated cardiovascular risk. Cholesteryl ester transfer protein (CETP) lowers HDL-C by transferring cholesterol esters to LDL and VLDL particles. We tested the hypothesis that CETP activity is associated with CVE in patients with CKD stage V. We measured CETP activity and cholesterol levels in 69 haemodialysis patients. CVE and death were prospectively assessed over a follow-up period of 48 months. CETP activity was negatively correlated with HDL-C levels in patients without lipid-lowering medication (r = -0.379, P = 0.005). We found no difference in CETP activity in patients with cardiovascular disease at baseline compared to patients without cardiovascular disease. The same was true for incident CVE during the follow-up. When stratifying patients by median CETP activity, patients with high CETP activity did not have an increased risk for CVE (P = 0.901 by the log-rank test) or death (P = 0.615). Similarly, after stratifying patients by median HDL-C no increased risk for CVE (P = 0.780) or death (P = 0.838) was found in patients with low HDL-C. In summary, although CETP activity correlated with HDL-C levels, neither high CETP activity nor low HDL-C was associated with CVE in CKD stage V patients. Thus, pharmacological modification of HDL-C by CETP inhibitors seems to be of questionable value in these patients.

TaqI B1/B2 and -629A/C cholesteryl ester transfer protein (CETP) gene polymorphisms and their association with CETP activity and high-density lipoprotein cholesterol levels in a Tehranian population. Part of the Tehran Lipid and Glucose Study (TLGS)

We examined the cholesteryl ester transfer protein (CETP) gene TaqI intron 1 B1/B2 polymorphism and the -629A/C CETP promoter polymorphism in respect to high-density lipoprotein cholesterol (HDL-C) in a healthy Iranian population taken from the Tehran Lipid and Glucose Study (TLGS). The relationship between CETP activity and HDL-C level was also determined along with body mass index, blood pressure and tobacco smoking status. PCR-RFLP used to amplify a segment of the CETP intron 1 TaqI (B2/B1) polymorphism from 1021 individuals and we selected 345 individuals from the lowest, middle and highest HDL-C deciles and investigated the -629A/C polymorphism. We also evaluated the CETP activity of 103 of these individuals, each with at least one homozygous allele. The presence of the TaqI B2 and -629A/C A alleles were significantly associated with increased HDL-C levels (B2B2 = 1.19 ± 0.31 mmolL-1 vs. B1B1 = 1.01 ± 0.2 mmol L-1 for p < 0.001; AA = 1.15 ± 0.41 mmol L-1 vs. CC = 0.95 ± 0.28 mmol L-1 for p < 0.001) and decreased the CETP activity (B1B1 = 67.8 ± 8.9 pmol L-1 vs. B2B2 = 62.6 ± 9.6 pmol L-1 for p < 0.01; CC = 68.6 ± 8.4 pmol L-1 vs. AA = 62.7 ± 9.7 pmol L-1 for p < 0.002). The frequencies were 0.382 for the TaqI B2 allele and 0.462 for the -629A/C A allele, with linkage disequilibrium analysis giving D = 0.0965 and D' = 0.4695. We demonstrated that the TaqI B1 and B2 alleles and the -629A/C A and C alleles were in linkage disequilibrium in our population and that there was a significant association between the B2 and A alleles and high HDL-C levels and low CETP activity. Linkage disequilibrium between the TaqI A and B2 alleles also detected.

Cholesteryl ester transfer protein TaqIB polymorphism and its relation to parameters of the insulin resistance syndrome in an Austrian cohort

The cholesteryl ester transfer protein (CETP) is responsible for the exchange of triglycerides and cholesteryl esters between lipoprotein particles leading to an increased hepatic clearance of HDL-cholesteryl esters. A high CETP activity reduces serum HDL levels, whereas persons without CETP activity have high HDL levels. We investigated the association of the TaqIB CETP polymorphism and various parameters of the insulin resistance syndrome in a cross sectional population based study. We included 1029 persons without known cardiovascular disease or diabetes mellitus consecutively enrolled in our SAPHIR program (Salzburg Atherosclerosis Prevention program in persons with a High Infarction Risk). Numerous clinical and laboratory data were accomplished. Insulin sensitivity was measured by a short insulin tolerance test. The TaqIB CETP polymorphism was determined by PCR, TaqI restriction and electrophoresis. 35.2% were homozygous for the prevalence (B1B1), 46.7% were heterozygous (B1B2), and 18.1% homozygous for the absence (B2B2) of the restriction site. HDL cholesterol and apolipoprotein A1 were lower and small dense low-density lipoproteins (sdLDL) higher in B1B1 compared to B2B1 and B2B2 persons. In women, we found a significant interaction effect between CETP genotype and adiposity for HDL cholesterol. B1B1 women with a BMI and a waist circumference above the median had 9.7 mg/dl lower HDL than B1B2 and 9.1 mg/dl lower HDL than B2B2 women ( P < 0.001). In men, no interaction effect but a marked genotype to HDL correlation was found. There was a high CETP effect on sdLDL detected in men ( P = 0.001). B1B1 men had sdLDL in 36%, B1B2 in 24.6%, and B2B2 in only 14.5%. Men with adiposity and insulin resistance had twice as many sdLDL as insulin sensitive men. We found a significant sex specific effect of the TaqIB CETP polymorphism on the insulin resistance parameters HDL-cholesterol and sdLDL in an Austrian population based study.

The relationship between plasma high density lipoprotein cholesterol levels and cholesteryl ester transfer protein activity in six species of healthy experimental animals.

Plasma high-density lipoprotein cholesterol (HDL-C) concentrations are regulated by plasma cholesteryl ester transfer protein (CETP) in humans. The aim of this study was to ascertain the relationship between plasma HDL-C and plasma CETP activities in mouse, rat, dog, hamster, rabbit and monkey. In this study, the plasma HDL-C levels were highest in dogs and lowest in rabbits among the six species. Plasma CETP activities were higher in hamsters, rabbits and monkeys compared to mice, rats and dogs. The present study shows that there are species differences in HDL-C and CETP activity in six species of healthy experimental animals, with the six species being separated into two types. The first type showed a high HDL-C/TC ratio with low or absent CETP activity, and included mouse, rat and dog, whereas the second type showed a low HDL-C/TC ratio and high CETP activity, and included hamster, rabbit and monkey. The present study also shows that there is a strong relationship between plasma HDL-C levels and CETP activity in high CETP activity animals and that the relationship between the HDL-C/TC ratio and CETP activity is an important factor in all animals, regardless of CETP activity level.

Plasma cholesteryl ester transfer protein activity is high in infants and is not affected by thyroid hormones

We investigated the effects of thyroid dysfunction on cholesteryl ester transfer protein (CETP) by studying plasma CETP activity in hypothyroid infants before and after they were rendered euthyroid by L-thyroxine (LT4) replacement therapy. To exclude environmental factors possibly affecting plasma CETP activity, we selected hypothyroid infants to study plasma CETP activity. Plasma CETP activity was measured as the rate of radiolabeled cholesteryl ester transfer from high-density lipoprotein (HDL) to serum apolipoprotein B (apo B)—containing lipoproteins in plasma from 14 hypothyroid infants before and 2 months after LT4 replacement, 23 normal infants, and 61 normal adults. Relationships between CETP and thyroid hormones were examined separately in the 14 hypothyroid infants and 32 euthyroid infants, including the 14 above-described hypothyroid infants and an additional 18 treated hypothyroid infants. Serum levels of thyrotropin (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were also determined on an autoanalyzer system in our hospital. In contrast to previous reports, we found no differences in plasma CETP activity between hypothyroid infants and age-matched normal infants. LT4 substitution did not cause any changes in plasma CETP activity after therapy. Plasma CETP activity showed no correlation with serum TSH, FT4, and FT3 levels. Both hypothyroid and normal infants were found to have significantly higher plasma CETP activity than normal adults. From these results, we conclude that in infants thyroid hormones do not affect plasma CETP activity, and normal infants have high plasma CETP activity, compared with normal adults.

Cholesteryl ester transfer protein gene polymorphisms are associated with carotid atherosclerosis in men.

The cholesteryl ester transfer protein (CETP) is involved in the reverse cholesterol transport and is therefore a candidate gene for atherosclerosis. The prevalences of the I405V and the R451Q polymorphisms were studied in a population sample of 515 men and women. Genotypes were determined by PCR and carotid atherosclerosis by ultrasonography as the mean intima-media thickness (IMT) of the carotid arteries. The Q451 allele was associated with significantly lower intima media thickness in men (P = 0.001). The Q451 allele was, in our earlier study, associated with high plasma CETP activity in men. The VV405 genotype was associated with lower plasma CETP activity compared with the II405 genotype (P < 0.01 for the difference). In the general linear model general factorial procedure the interaction between alcohol consumption and the I405V genotype on IMT was significant (P = 0.013) in men, and when the interaction term was taken into the model the I405V genotype also significantly affected IMT (P = 0.008). The VV405 genotype seems to be most harmful for men with the highest alcohol consumption. We describe two polymorphisms of the CETP gene associated with intima media thickness in men. A significant interaction was found between alcohol consumption and the I405V genotype on IMT.

R451Q mutation in the cholesteryl ester transfer protein (CETP) gene is associated with high plasma CETP activity

Cholesteryl ester transfer protein (CETP), as a candidate gene for dyslipoproteinemia and coronary heart disease, was studied in 105 men with low plasma concentrations of high density lipoprotein cholesterol (HDL-C) and established coronary heart disease as well as in 515 randomly selected men and women. A one-nucleotide substitution (G to A) in exon 15, which changes arginine (451) to glutamine in CETP protein, was detected by PCR-SSCP and direct sequencing and screened in the population sample by a simple PCR-based restriction assay. In the random population sample the allele frequency of the R451Q mutation was 1.9%. Men heterozygous for the R451Q mutation ( n=7) had 27% higher CETP activity than age-, body mass index-, smoking- and alcohol consumption-matched controls with normal genotype ( n=21; P=0.003). Women heterozygous for the R451Q mutation ( n=7) had 16% lower total cholesterol compared to matched controls ( n=21; P=0.07), but no such difference was detected in men. In the random population sample the correlation between plasma total cholesterol level and CETP activity was 0.19 ( P=0.044), both in men and women. When women with total cholesterol over 5.2 mmol/l were excluded from analysis, heterozygotes ( n=4) had plasma CETP activity of 113 nmol/h/ml plasma, whereas those of normal genotype ( n=12) had 103 nmol/h/ml plasma, but this difference was not statistically significant. Women heterozygous for the R451Q mutation and consuming less than 10 g alcohol a week had 23% lower HDL-C compared to women with the normal genotype ( P=0.032). In conclusion, we describe a mutation in the CETP gene associated with high plasma CETP activity in men and with low total cholesterol in women. Further studies are needed to evaluate the effect of mutation on the risk of coronary heart disease.

EXERCISE ALTERS LIPID CONCENTRATIONS BUT NOT CETP ACTIVITY IN HYPER-AND NORMOCHOLESTEROLEMIC MEN 32

To study the effects of exercise on cholesteryl ester transfer protein activity (CETPa) and on selected blood lipid concentrations, blood samples were obtained from 13 untrained, hypercholesterolemic (HC) and 12 normocholesterolemic (NC) men of similar age and weight (combined [horizontal bar over]x ± SEM = 44 ± 1 yr and 86 ± 4 kg, respectively) at four time points; before (PRE), then immediately (IPE), 24 h, and 48 h after treadmill exercise (70% ˙VO2max, 500 kcal). Concentrations were adjusted for plasma volume changes. RESULTS. The table shows significant effects (p < 0.05) from 2 (GROUP) × 4 (TIME) ANOVA with repeats on TIME; no interactions were significant (values are [horizontal bar over]x ± SEM; * = group difference; row means with similar superscripts not different; lipid concentrations in mg/dL; CETPa in% cholesterol ester transferred / 4 h). Table CONCLUSIONS: 1) CETPa is not altered by exercise; 2) despite higher CETPa in HC men, postexercise changes in lipid concentrations do not differ from those in NC men of similar age and weight.