http://repub.eur.nl/res/aut/7687/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/26489/ 2011-05-01T00:00:00Z Context: Plasma lipoprotein-associated phospholipase A2(Lp-PLA2) predicts incident cardiovascular disease and is associated preferentially with negatively charged apolipoprotein B-containing lipoproteins. The plasma cholesteryl ester transfer (CET) process, which contributes to low highdensity lipoprotein cholesterol and small, dense low-density lipoproteins, is affected by the composition and concentration of apolipoprotein B-containing cholesteryl ester acceptor lipoproteins. Objective: We tested relationships of CET with Lp-PLA2in subjects with and without metabolicsyndrome (MetS). Design and Setting: In 68 subjects with MetS and 74 subjects without MetS, plasma Lp-PLA2mass, cholesterol esterification (EST), lecithin:cholesterol acyltransferase (LCAT) activity level, CET, CET protein (CETP) mass, and lipoproteins were measured. Results: EST, LCAT activity, CET (P<0.001 for all), and CETP (P<0.030) were increased, and Lp-PLA2was decreased (P<0.043) in MetS. CET was correlated positively with Lp-PLA2in subjects with and without MetS (P = 0.05 for both). EST and LCAT activity were unrelated to Lp-PLA2, despite a positive correlation between EST and CET (P = 0.001). After controlling for age, sex, and diabetes status, CET was determined by Lp-PLA2in the whole group (β = 0.245; P = 0.001), and in subjects with (β = 0.304; P = 0.001) and without MetS (β = 0.244; P = 0.006) separately, independently of triglycerides and CETP. Conclusions: PlasmaCETis related to Lp-PLA2in subjects withandwithout MetS.Theprocess of CET, but not EST, may be influenced by Lp-PLA2. These findings provide a rationale to evaluate whether maneuvers that inhibit Lp-PLA2will reduce CET, and vice versa to document effects of CETP inhibition on Lp-PLA2. Copyright http://repub.eur.nl/res/pub/21625/ 2010-11-01T00:00:00Z Purpose: Plasma apolipoprotein M (apoM) is potentially anti-atherogenic, and has been found to be associated positively with plasma total, LDL and HDL cholesterol in humans. ApoM may, therefore, be intricately related to cholesterol metabolism. Here, we determined whether plasma apoM is affected by statin or fibrate administration in patients with diabetes mellitus. Methods: Fourteen type 2 diabetic patients participated in a placebo-controlled crossover study which included three 8-week treatment periods with simvastatin (40 mg daily), bezafibrate (400 mg daily), and their combination. Results: ApoM was decreased by 7% in response to simvastatin (P< 0.05 from baseline and placebo), and remained unchanged during bezafibrate and combined simvastatin. +. bezafibrate administration. Plasma apoM concentrations correlated positively with apoB-containing lipoprotein measures at baseline and during placebo (P< 0.02 to P< 0.001), but these relationships were lost during all lipid lowering treatment periods. Conclusions: This study suggests that, even though plasma apoM is lowered by statins, apoM metabolism is to a considerable extent independent of statin- and fibrate-affected pathways involved in cholesterol homeostasis. http://repub.eur.nl/res/pub/21035/ 2010-08-03T00:00:00Z Background-In contrast to clear associations between variants in genes participating in low-density lipoprotein metabolism and cardiovascular disease risk, such associations for high-density lipoprotein (HDL)-related genes are not well supported by recent large studies. We aimed to determine whether genetic variants at the locus encoding phospholipid transfer protein (PLTP), a protein involved in HDL remodeling, underlie altered PLTP activity, HDL particle concentration and size, and cardiovascular disease risk. Methods and Results-We assessed associations between 6 PLTP tagging single nucleotide polymorphisms and PLTP activity in 2 studies (combined n=384) and identified 2 variants that show reproducible associations with altered plasma PLTP activity. A gene score based on these variants is associated with lower hepatic PLTP transcription (P=3.2×10-18) in a third study (n=957) and with an increased number of HDL particles of smaller size (P=3.4×10-17) in a fourth study (n=3375). In a combination of 5 cardiovascular disease case-control studies (n=4658 cases and 11 459 controls), a higher gene score was associated with a lower cardiovascular disease risk (per-allele odds ratio, 0.94; 95% confidence interval, 0.90 to 0.98; P=1.2×10-3; odds ratio for highest versus lowest gene score, 0.69; 95% confidence interval, 0.55 to 0.86; P=1.0×10-3). Conclusions-A gene score based on 2 PLTP single nucleotide polymorphisms is associated with lower PLTP transcription and activity, an increased number of HDL particles, smaller HDL size, and decreased risk of cardiovascular disease. These findings indicate that PLTP is a proatherogenic entity and suggest that modulation of specific elements of HDL metabolism may offer cardiovascular benefit. http://repub.eur.nl/res/pub/27538/ 2010-01-01T00:00:00Z Background: Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target. Methods and Results: We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI-0.28 to 0.60 mm Hg) and diastolic blood pressure (-0.04 mm Hg, 95% CI-0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib. Conclusions: Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans. http://repub.eur.nl/res/pub/28408/ 2010-01-01T00:00:00Z Lecithin:cholesterol acyltransferase (LCAT) is instrumental in high-density lipoprotein (HDL) maturation, but high LCAT levels do not predict low cardiovascular risk. LCAT may affect antioxidative or anti-inflammatory properties of HDL. We determined the relationship of plasma high-sensitivity C-reactive protein (CRP) with LCAT activity and evaluated whether LCAT activity modifies the decreasing effect of HDL cholesterol (HDL-C) on CRP, as an estimate of its anti-inflammatory properties. Plasma HDL-C, apolipoprotein (apo) A-I and LCAT activity (exogenous substrate method) were measured in 260 nondiabetic men without cardiovascular disease. CRP was correlated inversely with HDL-C and apo A-I, and positively with LCAT activity (P < 0.01 to 0.001). Multivariate regression analysis demonstrated that age- and smoking-adjusted plasma CRP levels were associated negatively with HDL-C (β = - 0.224, P < 0.001) and positively with LCAT activity (β = 0.119, P = 0.034), as well as with the interaction between HDL-C and LCAT activity (β = 0.123, P = 0.026). There was also an interaction between apo A-I and LCAT activity on CRP (β = 0.159, P = 0.005). These relationships remained similar after adjustment for apo B-containing lipoproteins. In conclusion, the inverse relationship of HDL-C with CRP is attenuated by LCAT activity at higher HDL-C levels. It is hypothesized that LCAT could mitigate HDL's anti-inflammatory or antioxidative properties at higher HDL-C concentrations. http://repub.eur.nl/res/pub/16231/ 2009-08-01T00:00:00Z Atorvastatin lowers plasma phospholipid transfer protein (PLTP) activity, which stimulates pre-β-HDL generation in vitro. We determined the effect of atorvastatin on pre-β-HDL formation and its relation with PLTP activity in type 2 diabetes. Methods: Plasma pre-β-HDL formation as well as plasma apo A-I, LpA, LpAI:AII, cholesteryl ester transfer protein (CETP) and PLTP activity were measured before and after 30 weeks treatment in 40 patients randomized to atorvastatin 80 mg daily and 41 placebo receiving patients. Pre-β HDL formation was measured by crossed immunoelectrophoresis under conditions of lecithin:cholesterol acyltransferase (LCAT) inhibition. Results: Plasma pre-β-HDL formation, triglycerides, LDL cholesterol, PLTP activity, and CETP decreased after statin treatment (all P < 0.001 vs placebo), whereas HDL cholesterol increased (P < 0.005). Plasma apo A-I, LpAI and LpAI:AII remained unchanged compared to placebo. In all patients combined, the changes in pre-β-HDL formation were independently related to the decrease in plasma triglycerides (β = 0.31; P = 0.006) and PLTP activity (β = 0.23; P = 0.038), without a contribution of CETP. In the atorvastatin treated patients, the decrease in pre-β-HDL formation tended to be related to the decrease in PLTP activity (β = 0.30, P = 0.061) after controlling for decreases in triglycerides (β = 0.22, P = 0.22). Conclusion: High dose atorvastatin decreases the capacity of plasma to generate pre-β-HDL particles in type 2 diabetic patients, probably via lowering of plasma PLTP activity and triglycerides. This could contribute to an improvement in the atherogenic lipoprotein profile. http://repub.eur.nl/res/pub/25396/ 2009-07-01T00:00:00Z Objectives: Non-HDL-cholesterol (non-HDL-C) and apolipoprotein (apo) B are proposed as treatment targets. The extent to which statin therapy affects relationships of LDL-C and non-HDL-C with apoB was examined in type 2 diabetes. Methods: Analyses were performed in 217 hypertriglyceridaemic type2 diabetic patients (Diabetes Atorvastatin Lipid Intervention (DALI) cohort). 61patients randomized to placebo, 70 to 10mg atorvastatin daily and 65 - 80mg atorvastin daily completed follow-up. Results: Baseline fasting LDL-C of 2.42 mmol/l and non-HDL-C of 3.69 mmol/l corresponded to the apoB guideline target of 0.90 g/l. During atorvastatin (10 and 80 mg daily), the LDL-C target was achieved most frequently, and lower LDL-C (2.38 and 2.29 mmol/l) and non-HDL-C (3.24 and 3.19 mmol/l) concentrations corresponded to this apoB goal. Decreases in LDL-C during atorvastatin treatment were negatively related (p < 0.001), but decreases in non-HDL-C were positively related to changes in triglycerides (p < 0.001), independently from decreases in apoB (p < 0.001 for all). Decreases in LDL-C and non-HDL-C were positively associated with decreases in cholesteryl ester transfer protein mass (p < 0.001). Conclusions: During atorvastatin lower LDL-C and non-HDL-C levels correspond to the apoB guideline target, which would favour its use as treatment target. http://repub.eur.nl/res/pub/18394/ 2009-03-01T00:00:00Z Background: The high-density lipoprotein (HDL)-associated anti-oxidative and anti-inflammatory enzyme, paraoxonase-I, has been found previously to be lower in type 2 diabetes mellitus. We studied whether statin and fibrate treatment, alone and in combination, affect serum paraoxonase-I activity in conjunction with changes in HDL cholesterol in diabetic patients. Subjects and methods: A placebo-controlled crossover study was carried out in 14 type 2 diabetic patients to test the effect of 8 weeks of active treatment with simvastatin (40 mg daily), bezafibrate (400 mg daily), and their combination on serum paraoxonase-I activity, measured as its activity towards arylesterase and paraoxon. Serum paraoxonase-I activity was also compared between these diabetic patients and 49 non-diabetic control subjects. Results: Serum arylesterase activity was lower in type 2 diabetic patients compared to control subjects (P < 0·001), but the difference in paraoxonase activity was not significant (P = 0·22). Neither arylesterase (P = 0·24) nor paraoxonase activity (P = 0·37) was increased in response to treatment, despite higher HDL cholesterol and apolipoprotein A-I during combination therapy (P < 0·05 for both). Conclusion: Short-term administration of simvastatin and bezafibrate, even when combined, is ineffective in raising serum paraoxonase-I activity in type 2 diabetes. http://repub.eur.nl/res/pub/28736/ 2008-12-01T00:00:00Z Context: Lecithin:cholesterol acyltransferase (LCAT), which esterifies free cholesterol to cholesteryl esters, is required for normal plasma lipoprotein structure and is instrumental in high density lipoprotein (HDL) remodeling, but the relationship of variation in plasma LCAT activity with subclinical atherosclerosis is unclear. Objectives: The aim of the study was to determine the effect of the metabolic syndrome (MetS) on plasma LCAT activity and its relationship with carotid artery intima media thickness (IMT). Setting: The study was conducted at the vascular laboratory of a university medical center. Methods: In 74 subjects with MetS and 90 subjects without MetS (National Cholesterol Education Program Adult Treatment Panel III criteria), mean carotid artery IMT, plasma lipids, LCAT activity (exogenous substrate method), high-sensitive C-reactive protein, and homeostasis model assessment insulin resistance (HOMAir) were documented. Results: IMT was greater (P = 0.01) and plasma LCAT activity was higher (P < 0.001) in subjects with MetS compared to subjects without MetS. Similar increases in IMT and LCAT were found in MetS subjects without type 2 diabetes mellitus. Multiple linear regression analysis demonstrated that plasma LCAT activity was independently and positively related to HOMAir, plasma triglycerides, non-HDL cholesterol, and HDL cholesterol (all P < 0.001). After adjustment for age and sex, IMT was positively associated with LCAT activity (P < 0.01), independently of the presence of MetS (or alternatively of plasma lipids), HOMAir, and high-sensitive C-reactive protein. Conclusions: Plasma LCAT activity is elevated in MetS and may be a marker of subclinical atherosclerosis. Our findings do not support the contention that strategies to elevate LCAT are necessarily beneficial for cardioprotection. Copyright http://repub.eur.nl/res/pub/29639/ 2008-03-01T00:00:00Z Background: The extent to which plasma phospholipid transfer protein (PLTP) activity is affected by type 2 diabetes mellitus (DM) and metabolic syndrome (MetS) is still unknown. PLTP is synthesized in the liver, and elevated serum transaminases are considered to predict nonalcoholic fatty liver disease (NAFLD). In this study, we examined the relationship between plasma PLTP activity and liver enzymes in subjects with and without DM and MetS. Design: Plasma PLTP activity, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured in 71 subjects without DM or MetS, 21 without DM but with MetS, 26 with DM but without MetS and 55 with DM and MetS (WHO and NCEP-ATP III criteria). Results: After controlling for age, sex and alcohol intake, PLTP activity was positively related to both MetS (P < 0.001) and DM (P = 0.001). Serum ALT (P = 0.006) and AST (P = 0.04) were both associated with MetS, but only ALT was associated with DM (P < 0.001). In multiple linear regression models, serum ALT and AST were positively and independently associated with PLTP activity (P < 0.01 for all), even when the presence of MetS and DM was taken into account, as well as after controlling for glycated haemoglobin (HbA1c), insulin resistance, triglycerides, free fatty acids (FFA), C-reactive protein (CRP), leptin and adiponectin. Conclusions: Plasma PLTP activity is determined by MetS and by diabetes per se. Serum transaminases are independently associated with PLTP activity. We suggest that this lipid transfer protein may be a marker for NAFLD. http://repub.eur.nl/res/pub/29040/ 2008-02-01T00:00:00Z We tested whether hypertriglyceridemia associated with type 2 diabetes mellitus is accompanied by alterations in pre β-HDL, which are considered to be initial acceptors of cell-derived cholesterol, and by changes in the ability of plasma to promote cellular cholesterol efflux. In 28 hypertriglyceridemic and 56 normotriglyceridemic type 2 diabetic patients, and in 56 control subjects, we determined plasma lipids, HDL cholesterol and phospholipids, plasma pre β-HDL and pre β-HDL formation, phospholipid transfer protein (PLTP) activity, plasma cholesterol esterification (EST) and cholesteryl ester transfer (CET) and the ability of plasma to stimulate cholesterol efflux out of cultured human fibroblasts. HDL cholesterol and HDL phospholipids were lower, whereas plasma PLTP activity, EST and CET were higher in hypertriglyceridemic diabetic patients than in the other groups. Pre β-HDL levels and pre β-HDL formation were unaltered, although the relative amount of pre β-HDL (expressed as % of total plasma apo A-I) was increased in hypertriglyeridemic diabetic patients. Cellular cholesterol efflux to plasma from hypertriglyceridemic diabetic patients was increased compared to efflux to normotriglyceridemic diabetic and control plasma, but efflux to normotriglyceridemic diabetic and control plasma did not differ. Multiple linear regression analysis demonstrated that cellular cholesterol efflux to plasma was positively and independently related to pre β-HDL formation, PLTP activity and EST (multiple r = 0.48), but not to the diabetic state. In conclusion, cholesterol efflux from fibroblasts to normotriglyceridemic diabetic plasma is unchanged. Efflux to hypertriglyceridemic diabetic plasma is enhanced, in association with increased plasma PLTP activity and cholesterol esterification. Unaltered pre β-HDL formation in diabetic hypertriglyceridemia, despite low apo A-I, could contribute to maintenance of cholesterol efflux. http://repub.eur.nl/res/pub/29826/ 2008-01-01T00:00:00Z Objective: We tested whether in metabolic syndrome (MetS) subjects the ability of plasma to stimulate cellular cholesterol efflux, an early step in the anti-atherogenic reverse cholesterol transport pathway, is maintained despite low high-density lipoprotein (HDL) cholesterol. Design: In 76 subjects with and 94 subjects without MetS based on the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, we determined plasma (apo)lipoproteins, pre-β-HDL formation, phospholipid transfer protein (PLTP) activity, cholesterol esterification (EST), cholesteryl ester transfer (CET), adiponectin, and the ability of plasma from each subject to stimulate cholesterol efflux out of cultured fibroblasts obtained from a single donor. Results: Apo E, PUP activity EST, and CET were higher (P = 0.04 to < 0.001), whereas adiponectin was lower in MetS subjects (P < 0.01). Pre-β-HDL and pre-β-HDL formation were not different between subjects with and without MetS. Cellular cholesterol efflux to plasma from MetS subjects was slightly higher versus plasma from subjects without MetS (8.8 ± 1.0 vs 8.5 ± 0.9%, P=0.05), but the difference was not significant after age, sex, and diabetes adjustment. Cellular cholesterol efflux was positively related to pre-β-HDL formation, EST, PLTP activity, and apo E (P < 0.05 for all by multiple linear regression analysis), without an independent association with MetS and diabetes status. Conclusions: The ability of plasma from MetS subjects to promote fibroblast cholesterol efflux is not defective, although HDL cholesterol is decreased. Higher cholesterol esterification, PLTP activity, and apo E levels may contribute to the maintenance of cholesterol efflux in MetS. http://repub.eur.nl/res/pub/30233/ 2008-01-01T00:00:00Z A recent population-based study showed that cholesteryl ester transfer protein (CETP) gene variations, which relate to lower plasma CETP, may predict increased cardiovascular risk, in spite of higher HDL cholesterol. Among other functions, CETP activity contributes to cellular cholesterol efflux, an early step in the anti-atherogenic reverse cholesterol transport (RCT) process. We hypothesized that cellular cholesterol efflux stimulating capacity of plasma could be associated with CETP gene variation. In this study, we tested the extent to which the ability of plasma to promote cholesterol efflux from cultured human fibroblasts is associated with CETP gene variation. In 223 men, the - 629C→A CETP promoter polymorphism, plasma lipids, CETP mass, cholesteryl ester transfer (CET), lecithin:cholesterol acyltransferase (LCAT) activity and the ability of plasma to promote cholesterol efflux from human skin fibroblasts, obtained from a single normolipidemic donor, were determined. In - 629CC homozygotes (n = 52), cholesterol efflux, plasma CETP mass, CET and LCAT activity were higher, whereas HDL cholesterol was lower compared to - 629 AA homozygotes (n = 62) and - 629CA + AA carriers (n = 171) (P < 0.05 to P < 0.001). Univariate correlation analysis showed that cellular cholesterol efflux was related to CETP genotype (P = 0.04), plasma CET (P<0.05), LCAT activity (P < 0.001) and apo A-I (P < 0.05). Multiple linear regression analysis confirmed the independent association of cellular cholesterol efflux to plasma with CETP genotype. In conclusion, an association of cellular cholesterol efflux with the - 629C→A CETP polymorphism, possibly also involving LCAT activity, could provide a mechanism explaining why CETP gene variation, which relates to lower plasma CETP, does not confer diminished cardiovascular risk. http://repub.eur.nl/res/pub/36061/ 2007-08-01T00:00:00Z http://repub.eur.nl/res/pub/36461/ 2007-06-01T00:00:00Z PURPOSE OF REVIEW: Type 2 diabetes frequently coincides with dyslipidemia, characterized by elevated plasma triglycerides, low high-density lipoprotein cholesterol levels and the presence of small dense low-density lipoprotein particles. Plasma lipid transfer proteins play an essential role in lipoprotein metabolism. It is thus vital to understand their pathophysiology and determine which factors influence their functioning in type 2 diabetes. RECENT FINDINGS: Cholesteryl ester transfer protein-mediated transfer is increased in diabetic patients and contributes to low plasma high-density lipoprotein cholesterol levels. Apolipoproteins A-I, A-II and E are components of the donor lipoprotein particles that participate in the transfer of cholesteryl esters from high-density lipoprotein to apolipoprotein B-containing lipoproteins. Current evidence for functional roles of apolipoproteins C-I, F and A-IV as modulators of cholesteryl ester transfer is discussed. Phospholipid transfer protein activity is increased in diabetic patients and may contribute to hepatic very low-density lipoprotein synthesis and secretion and vitamin E transfer. Apolipoprotein E could stimulate the phospholipid transfer protein-mediated transfer of surface fragments of triglyceride-rich lipoproteins to high-density lipoprotein, and promote high-density lipoprotein remodelling. SUMMARY: Both phospholipid and cholesteryl ester transfer proteins are important in very low and high-density lipoprotein metabolism and display concerted actions in patients with type 2 diabetes. http://repub.eur.nl/res/pub/35424/ 2007-05-01T00:00:00Z Content: Adiponectin has antiinflammatory and vascular protective effects and may improve insulin sensitivity. Animal data suggest a role of the renin-angiotensin aldosterone system (RAAS) in the regulation of adiponectin. Objective: Our objective was to investigate the role of the RAAS in regulation of adiponectin in humans in vivo. To this purpose we studied the effects of physiological (change in sodium status) and pharmacological modulation of RAAS activity (angiotensin II infusion and enalapril treatment) on plasma adiponectin. Design, Setting, and Patients: Thirty-five healthy male volunteers (aged 26 ± 9 yr) were studied after two 7-d periods: one on a lowsodium diet (LS, 50 mmol Na+per day) and one on a high-sodium diet (HS, 200 mmol Na+per day). At the end of each period, adiponectin was measured, and its response to angiotensin II infusion (0.3, 1, and 3 ng/kg·min all during 1 h) was determined. Additionally, all subjects received 1 wk treatment of enalapril 20 mg once daily (angiotensin converting enzyme inhibition) during the HS. Main Outcome Measure: We measured plasma adiponectin concentrations during LS and HS and in response to angiotensin II infusion. Results: The suppression of the RAAS by HS elicited a significant rise in adiponectin [LS baseline, 11.9 (8.3-16.2) μg/liter; HS baseline, 14.4 (11.2-20.4) μg/liter; P < 0.05]. All doses of angiotensin II elicited a profound decrease in adiponectin during both conditions [LS 3 ng/kg·min, 7.4 (6.3-8.9) μg/liter; HS 3 ng/kg·min, 8.4 (7.3-9.9) μg/liter; both P < 0.001 vs. baseline]. Angiotensin converting enzyme inhibition induced a significant rise in adiponectin [16.6 (10.6-20.9) μg/liter, P < 0.05 vs. HS]. Conclusion: Physiological and pharmacological modulation of RAAS affects plasma adiponectin with lower concentrations during the high angiotensin II conditions. The therapeutic potential of RAAS blockade as a tool to correct hypoadiponectinemia should be explored further. Copyright http://repub.eur.nl/res/pub/35827/ 2007-04-01T00:00:00Z Aims: High cholesteryl ester transfer protein (CETP) concentrations are associated with increased risk of cardiovascular disease (CVD) in subjects with high triglycerides. We determined the relationship of plasma CETP with incident CVD in a population with relatively low triglycerides. Methods and results: A nested case-control study was performed in men participating in the prospective PREVEND study, after exclusion of CVD, diabetes mellitus, and lipid-lowering drugs use at baseline. Plasma CETP was measured in 111 men who developed a cardiovascular event (cases) during follow-up and in 116 controls who remained free of CVD. Fasting total cholesterol (P < 0.001) and triglycerides (P < 0.001) were higher, HDL cholesterol was lower (P = 0.001), but CETP was similar in cases and controls (P = 0.39). Cox proportional hazards regression analysis showed that CVD risk tended to be lower with higher plasma CETP after adjustment for age and lipids (hazard ratio 0.84; 95% CI 0.69-1.03, P = 0.10). Plasma CETP was lower in cases than in controls (P = 0.05) with triglycerides ≤ 1.38 mmol/L (median), but not with higher triglycerides. The age-adjusted hazard ratio for CVD was 0.46 (95% CI 0.24-0.90) in men with triglycerides ≤ 1.38 mmol/L and CETP > 2.26 mg/L (median) compared with men with similarly low triglycerides and CETP ≤ 2.26 mg/L. With higher triglycerides, the hazard ratio for CVD was similar in both CETP categories. Conclusion: Relatively high plasma CETP may favour reduced CVD risk in the context of low triglycerides. http://repub.eur.nl/res/pub/36808/ 2007-04-01T00:00:00Z http://repub.eur.nl/res/pub/35580/ 2007-02-01T00:00:00Z In view of the cardioprotective effect of high-density lipoproteins (HDL) and the limited effects of statin and fibrate therapy on HDL cholesterol, it is clinically relevant to test whether pharmacological treatment aimed at raising HDL lowers cardiovascular risk. Cholesteryl ester transfer protein (CETP) is a new therapeutic target, because the cholesteryl ester transfer process lowers HDL cholesterol and contributes to an atherogenic lipoprotein profile, particularly when plasma triglycerides are high. Clinical evidence suggests that coronary artery calcification as well as intima media thickness is positively related to plasma cholesteryl ester transfer, and that high plasma CETP concentration is associated with increased cardiovascular risk in hypertriglyceridaemia. However, CETP could also have anti-atherogenic potential, since it provides a potentially beneficial route for delivery of HDL-derived cholesteryl esters to the liver. In addition, CETP could also favourably stimulate peripheral cell cholesterol removal and enhance hepatic cholesterol uptake. Recent evidence suggests that a high CETP level may confer lower cardiovascular risk in the context of low triglycerides. At maximal doses, the CETP inhibitors JTT-705 and torcetrapib elicit a marked rise in HDL cholesterol of up to 34% and 91-106%, respectively. The effectiveness of these drugs on (intermediate) clinical outcome measures is currently being tested in large-scale phase III clinical trials, with torcetrapib being only evaluated in combination therapy with atorvastatin. When and how to use CETP inhibitors, e.g. in combination with a statin or a fibrate, is a major challenge. We propose that low HDL cholesterol in the context of high triglycerides, such as found in type 2 diabetes mellitus, could become an important indication area for this new class of drugs. http://repub.eur.nl/res/pub/36833/ 2007-01-01T00:00:00Z Adipose tissue contributes to plasma levels of lipid transfer proteins and is also the major source of plasma adipokines. We hypothesized that plasma cholesteryl ester transfer protein (CETP) mass, phospholipid transfer protein (PLTP) activity and cholesteryl ester transfer (CET, a measure of CETP action) are determined by adipokine levels. In this study, relationships of plasma CETP mass, PLTP activity and CET with leptin, resistin and adiponectin were analyzed in type 2 diabetic patients and control subjects. Plasma PLTP activity (P < 0.001), CET (P < 0.001), leptin (P = 0.003), resistin (P < 0.001), high sensitive C-reactive protein (P = 0.005), and insulin resistance (HOMAir) (P < 0.001) were higher, whereas HDL cholesterol (P < 0.001) and plasma adiponectin (P < 0.001) were lower in 83 type 2 diabetic patients (32 females) than in 83 sex-matched control subjects. Multiple linear regression analysis demonstrated that in diabetic patients plasma leptin levels were related to plasma CETP mass (P = 0.018) and PLTP activity (P < 0.001), but not to the other adipokines measured. Plasma CET was inversely correlated with adiponectin in univariate analysis, but this association disappeared in multivariate models that included plasma lipids and CETP. In conclusion, both plasma CETP mass and PLTP activity are associated with plasma leptin in type 2 diabetes. The elevated CET in these patients is not independently related to any of the measured plasma adipokines. http://repub.eur.nl/res/pub/9371/ 2000-01-01T00:00:00Z The effects of growth hormone (GH) replacement on plasma lecithin:cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), and phospholipid transfer protein (PLTP), factors involved in high density lipoprotein (HDL) metabolism, are unknown. We carried out a 6 months study in 24 GH-deficient adults who were randomized to placebo (n = 8), low dose GH (1 U daily, n = 8), and high dose GH (2 U daily, n = 8), followed by a 6 months open extension study with high dose GH (1 drop-out). No significant changes in plasma lipoproteins, LCAT, CETP, and PLTP activities, cholesterol esterification (EST) and cholesteryl ester transfer (CET) were observed after placebo. After 6 months of GH (combined data, n = 24), very low + low density lipoprotein (VLDL + LDL) cholesterol (P < 0.05) and apolipoprotein B (P < 0.05) decreased, whereas HDL cholesterol and HDL cholesteryl ester increased (P < 0. 05). Prolonged treatment showed comparable effects. Plasma apolipoprotein A-I and Lp[a] remained unchanged. Plasma LCAT (P < 0. 01) and CETP activities (P < 0.01), as well as EST (P < 0.01) and CET decreased (P < 0.01) after 12 months of GH (n = 15), but PLTP activity did not significantly change. Changes in EST and CET after 12 months of treatment were independently related to changes in plasma LCAT (P = 0.001 and CETP activity (P = 0.01). In conclusion, GH replacement therapy improves the lipoprotein profile in GH-deficient adults. Chronic GH replacement lowers plasma LCAT and CETP activities, contributing to a decrease in cholesterol esterification and cholesteryl ester transfer. These effects may have consequences for HDL metabolism and reverse cholesterol transport. http://repub.eur.nl/res/pub/9141/ 1999-01-01T00:00:00Z Lecithin:cholesteryl acyl transferase (LCAT), cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP), and lipoprotein lipases are involved in high density lipoprotein (HDL) metabolism. We evaluated the influence of insulin sensitivity and of the TaqIB CETP gene polymorphism (B1B2) on plasma LCAT, CETP, and PLTP activities (measured with exogenous substrates) and their responses to hyperinsulinemia. Thirty-two non-diabetic men without hyperlipidemia were divided in quartiles of high (Q(1)) to low (Q(4)) insulin sensitivity. Plasma total cholesterol, very low + low density lipoprotein cholesterol, triglycerides, and apolipoprotein (apo) B were higher in Q(4) compared to Q(1) (P < 0.05 for all), whereas HDL cholesterol and apoA-I were lowest in Q(4) (P < 0.05 for both). Plasma LCAT activity was higher in Q(4) than in Q(1) (P < 0. 05) and PLTP activity was higher in Q(4) than in Q(2) (P < 0.05). Insulin sensitivity did not influence plasma CETP activity. Postheparin plasma lipoprotein lipase activity was highest and hepatic lipase activity was lowest in Q(1). Insulin infusion decreased PLTP activity (P < 0.05), irrespective of the degree of insulin sensitivity. The CETP genotype exerted no consistent effects on baseline plasma lipoproteins and LCAT, CETP, and PLTP activities. The decrease in plasma PLTP activity after insulin was larger in B1B1 than in B2B2 homozygotes (P < 0.05). These data suggest that insulin sensitivity influences plasma LCAT, PLTP, lipoprotein lipase, and hepatic lipase activities in men. As PLTP, LCAT, and hepatic lipase may enhance reverse cholesterol transport, it is tempting to speculate that high levels of these factors in association with insulin resistance could be involved in an antiatherogenic mechanism. A possible relationship between the CETP genotype and PLTP lowering by insulin warrants further study.