Postprandial variations in the cholesteryl ester transfer protein activity, phospholipid transfer protein activity and plasma cholesterol efflux capacity in normolipidemic men

Syeda, Farisa; Senault, Claude; Delplanque, Bernadette; Roy, Brigitte Le; Thaminy, A.; Gripois, D.; Blouquit, Marie-France; Ruelland, A.; Mendy, F.; Lutton, C.

doi:10.1016/s0939-4753(03)80165-5

Cited by 16 publications

(8 citation statements)

References 43 publications

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“…However, our results are different from those published in two previous reports [16,17], in which postprandial PLTP activity remained nearly unchanged. The obvious difference between the present study and the others is the size of the population.…”

Section: Discussioncontrasting

confidence: 99%

Serum Phospholipid Transfer Protein Activity After a High Fat Meal in Patients with Insulin‐Treated Type 2 Diabetes

Schlitt

Schwaab²,

Fingscheidt³

et al. 2010

Lipids

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Plasma phospholipid transfer protein (PLTP) mediates both net transfer and exchange of phospholipids between different lipoproteins. Animal studies have shown that it is closely related to the development of atherosclerosis. Although many studies have indicated that PLTP activity is increased in diabetes mellitus, the role of PLTP in diabetes is still unclear. To evaluate the influence of a high-fat meal on PLTP activity, 50 nondiabetic patients with coronary heart disease (CHD), 50 insulin-treated Type 2 diabetics, and 50 healthy controls were included. We determined PLTP activity before and 4 and 8 h after a high-fat meal. As expected, serum PLTP activity was significantly higher in CHD patients than in healthy controls (71.0 +/- 46.2 vs. 54.0 +/- 33.8 pmol/microl/h, P = 0.032) at baseline. More importantly, we found that serum PLTP activity increased to its maximum 4 h after fat loading and then decreased to nearly basal levels after 8 h both in controls and CHD patients. In contrast, PLTP activity continuously increased during this time period in the diabetic patients. With regards to the data from this study we hypothesize that serum PLTP is involved in the clearance of postprandial lipoproteins and this process is attenuated in diabetes. Since postprandial lipoproteins are atherogenic, the delay in clearance of these particles could play an important role in the development of atherosclerosis in patients with diabetes mellitus.

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Section: Discussioncontrasting

confidence: 99%

Serum Phospholipid Transfer Protein Activity After a High Fat Meal in Patients with Insulin‐Treated Type 2 Diabetes

Schlitt

Schwaab²,

Fingscheidt³

et al. 2010

Lipids

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“…Imax = 98.6%; IC50 = 32.2 mg l -1 estimated using the Hill equation with a sigmoidicity factor of 1.1 Table 3 Incidence of subjects with treatment emergent adverse events by treatment group (all subjects treated, n = 38) of the serum sample to be analyzed and thus closely reflected the in vivo profile of enzyme activity under treatment. In the placebo-treated subjects, a trend to enhanced endogenous CETP activity was observed starting at the 6 h time point, which may be related to food intake (lunch) after the 4 h sampling time point as suggested by Syeda [26]. BAY 60-5521 and placebo were administered as an oral solution with non-sparkling water (total volume 240 ml).…”

Section: Figurementioning

confidence: 87%

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein

Boettcher

Heinig

Schmeck

et al. 2012

Brit J Clinical Pharma

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Keywordscholesteryl ester transfer protein, concentration-effect relationship, first in man, pharmacodynamics, pharmacokinetics ---------------------------------------------------------------------- WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of cholesterol esters from the cardioprotective high density lipoprotein cholesterol (HDL-C) to the proatherogenic low density lipoprotein cholesterol (LDL-C) and very low density lipoprotein cholesterol (VLDL-C) leading to lower concentrations of HDL-C but raising the concentrations of proatherogenic LDL-C and VLDL-C. • Inhibition of CETP is considered a potential approach to treat dyslipidaemia.• Phase III studies demonstrating no benefit in regard to the defined clinical end points with the CETP inhibitor torcetrapib challenged the future perspectives of CETP inhibitors as potential therapeutic agents although it has been recently discussed whether potential off-target effects of torcetrapib could have contributed to the failure of this CETP inhibitor.• It has been suggested in recent publications to continue studying other CETP inhibitors for their potential to improve plasma lipid profiles and reduce cardiovascular risk. Currently, several compounds are being investigated in preclinical or clinical studies. WHAT THIS STUDY ADDS• This study provides information on the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of a potential new treatment for dyslipidaemia.• Data from a first in man study with the new CETP inhibitor BAY 60-5521 are presented that demonstrate that BAY 60-5521 is clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL-C could be demonstrated. AIMSTo determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). METHODSThe first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n = 28) or were treated with a placebo (n = 10). RESULTSIn all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relativ...

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“…43 However, in other in vitro studies, no association between CETP activity in plasma and cholesterol efflux from Fu5AH cells was observed. 44,45 A cholesterol efflux-enhancing role for CETP was also observed in human CETP transgenic mice but not in rabbits. Serum of human transgenic (htg) apoA-I/ CETP mice showed an increased relative efflux efficiency per HDL particle compared with htg apoA-I mice, as assayed by measuring efflux from both cholesterol-loaded Fu5AH cells and fibroblasts.…”

Section: Availability Of Cholesterol Acceptor Particlesmentioning

confidence: 96%

Cholesteryl Ester Transfer Protein (CETP) Inhibition Beyond Raising High-Density Lipoprotein Cholesterol Levels

Klerkx

Harchaoui

Steeg

et al. 2006

ATVB

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Cholesteryl Ester Transfer Protein (CETP) Inhibition Beyond Raising High-Density Lipoprotein Cholesterol Levels Pathways by Which Modulation of CETP Activity May Alter AtherogenesisAnke H.E.M. Klerkx, Karim El Harchaoui, Wim A. van der Steeg, S. Matthijs Boekholdt, Erik S.G. Stroes, John J.P. Kastelein, Jan Albert KuivenhovenAbstract-Raising high-density lipoprotein cholesterol (HDL-C) is a promising strategy in the struggle to prevent cardiovascular disease, and cholesteryl ester transfer protein (CETP) inhibitors have been developed to accomplish this. The first results are encouraging, and, in fact, in rabbits, inhibition of CETP reduces atherosclerosis. Because human data regarding the reduction of atheroma burden require more time, the biochemical mechanisms underlying the putative atheroprotection of CETP inhibitors are currently dissected, and several pathways have emerged. First, CETP inhibition increases HDL-C and reduces low-density lipoprotein cholesterol (LDL-C) levels consistent with CETP lipid transfer activity and its role in reverse cholesterol transport (RCT). This coincides with putative beneficial increases in both HDL and LDL size. However, many aspects regarding the impact of CETP inhibition on the RCT pathway remain elusive, in particular whether the first step concerning cholesterol efflux from peripheral tissues to HDL is influenced. Moreover, the relevance of scavenger receptor BI and consequently the central role of HDL in human RCT is still unclear. Second, CETP inhibition was shown recently to increase antioxidant enzymes associated with HDL, in turn associated with decreased oxidation of LDL. Atheroprotection in man is currently anticipated based on the improvement of these biochemical parameters known to influence atherosclerosis, but final confirmation regarding the impact of CETP inhibition on cardiovascular outcome will have to come from trials evaluating clinical end points. [TGs]) between lipoproteins, and the causes and effects of natural variation in CETP activity, has been the subject of many reviews on CETP and CETP inhibition. 1-6 Therefore, we have chosen to summarize the current understanding of lipoprotein remodeling by CETP ( Figure, 1 and 2). Importantly, in dyslipidemias characterized by increased concentrations of TG-rich particles (mainly very low-density lipoprotein [VLDL] and VLDL remnants), the CE transfer from HDL shifts from LDL toward VLDL, particularly large VLDL1 (Figure, 2). 7,8 This is considered to be atherogenic because CE-enriched VLDLs become substrates for hepatic lipase (HL), resulting in the generation of deleterious small Simplified schematic representation of the effects of CETP inhibition on the RCT pathway and protection against inflammation and oxidation. The numbered flashes indicate impact areas of CETP inhibition, which are further detailed in the respective panels. Flashes with upward or downward arrows indicate upregulation and downregulation, respectively. Black arrows indicate transfer of free cholesterol (FC), CE, or TG; open arrows ...

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Postprandial variations in the cholesteryl ester transfer protein activity, phospholipid transfer protein activity and plasma cholesterol efflux capacity in normolipidemic men

Cited by 16 publications

References 43 publications

Serum Phospholipid Transfer Protein Activity After a High Fat Meal in Patients with Insulin‐Treated Type 2 Diabetes

Serum Phospholipid Transfer Protein Activity After a High Fat Meal in Patients with Insulin‐Treated Type 2 Diabetes

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein

Cholesteryl Ester Transfer Protein (CETP) Inhibition Beyond Raising High-Density Lipoprotein Cholesterol Levels

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