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Objective— Anacetrapib (ANA), an inhibitor of cholesteryl ester transfer protein (CETP) activity, increases plasma concentrations of high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (apoA)-I, apoA-II, and CETP. The mechanisms responsible for these treatment-related increases in apolipoproteins and plasma CETP are unknown. We performed a randomized, placebo (PBO)-controlled, double-blind, fixed-sequence study to examine the effects of ANA on the metabolism of HDL apoA-I and apoA-II and plasma CETP. Approach and Results— Twenty-nine participants received atorvastatin (ATV) 20 mg/d plus PBO for 4 weeks, followed by ATV plus ANA 100 mg/d for 8 weeks (ATV-ANA). Ten participants received double PBO for 4 weeks followed by PBO plus ANA for 8 weeks (PBO-ANA). At the end of each treatment, we examined the kinetics of HDL apoA-I, HDL apoA-II, and plasma CETP after D3-leucine administration as well as 2D gel analysis of HDL subspecies. In the combined ATV-ANA and PBO-ANA groups, ANA treatment increased plasma HDL-C (63.0%; P P P =0.002) without changes in production rate. Although the apoA-II levels increased by 12.6% ( P P P Conclusions— ANA treatment increases HDL apoA-I and CETP levels by decreasing the fractional clearance rate of each protein.

Background According to epidemiological studies, there is no clear relationship between the plasma cholesteryl ester transfer protein (CETP) concentration and the development of atherosclerosis in human populations. Although some studies suggest that increased CETP activity relates to undesirable profiles of plasma lipoproteins, promoting an anti-atherogenic plasma lipoprotein profile by drugs that inhibit CETP has not succeeded in preventing atherosclerosis in humans. Materials and Methods This review describes 28 investigations in human populations dealing with plasma CETP, 11 in mice that express human CETP and seven in animals (six in rabbits and one in mice) in which plasma CETP activity was inhibited by drugs. Results Present review shows that models in mice expressing human CETP are not illuminating because they report increase as well reduction of atherosclerosis. However, investigations in rabbits and mice that develop severe hypercholesterolaemia clearly indicate that impairment of the plasma CETP activity elicits protection against the development of atherosclerosis; in all of these experiments are attained substantial reductions of the atherogenic lipoproteins, namely, plasma apoB containing lipoproteins. Conclusion These models are strong indicators that the benefit in preventing atherosclerosis should be earned in cases of hyperlipidemia by CETP inhibitors.

Objective: To determine the effect of short-term weight loss in obese women on concentrations of plasma cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), two new risk factors for cardiovascular disease. Research Methods and Procedures: Plasma CETP and PLTP mass concentrations were measured in 38 obese, non-diabetic women before and after a moderate, 4% weight loss that was obtained by a 1250 kcal/d diet for 4 weeks. Anthropometric and biological parameters were measured before and after weight loss. Results: Plasma CETP concentration decreased substantially after weight loss (2.76 ± 0.79 before and 2.31 ± 0.69 mg/L after; p = 0.000), and the same was true for plasma PLTP concentration (9.01 ± 2.44 mg/L before vs. 8.34 ± 2.57 after; p = 0.043). The HDL profile shifted toward the small-sized range, with significant decreases in the relative abundance of HDL2b and HDL2a at the expense of HDL3b after weight loss. A significant, positive correlation between CETP and PLTP mass concentrations is reported for the first time in obese patients (r = 0.43, p = 0.004), and weight reduction was accompanied by early, concomitant, and parallel decreases in plasma CETP and PLTP levels (r = 0.47, p = 0.003). The significant relationship between CETP and PLTP levels was lost after the dietary intervention (r = 0.27; p = 0.11). Discussion: CETP and PLTP correlate positively and significantly in obese patients. The hypocaloric dietary manipulation constitutes a relevant intervention to reduce rapidly and simultaneously plasma levels of CETP and PLTP. The impact of reduced PLTP activity on HDL size appeared to be more prominent than the impact of concomitant reduction in CETP activity.

Plasma cholesteryl ester transfer protein (CETP) has a profound effect on neutral lipid transfers between HDLs and apolipoprotein B (apoB)-containing lipoproteins when it is expressed in combination with human apoA-I in HuAI/CETP transgenic (Tg) rodents. In the present study, human apoA-I-mediated lipoprotein changes in HuAI/CETPTg rats are characterized by 3- to 5-fold increments in the apoB-containing lipoprotein-to-HDL cholesterol ratio, and in the cholesteryl ester-to-triglyceride ratio in apoB-containing lipoproteins. These changes occur despite no change in plasma CETP concentration in HuAI/CETPTg rats, as compared with CETPTg rats. A number of HDL apolipoproteins, including rat apoA-I and rat apoC-I are removed from the HDL surface as a result of human apoA-I overexpression. Rat apoC-I, which is known to constitute a potent inhibitor of CETP, accounts for approximately two-thirds of CETP inhibitory activity in HDL from wild-type rats, and the remainder is carried by other HDL-bound apolipoprotein inhibitors. It is concluded that human apoA-I overexpression modifies HDL particles in a way that suppresses their ability to inhibit CETP. An apoC-I decrease in HDL of HuAI/CETPTg rats contributes chiefly to the loss of the CETP-inhibitory potential that is normally associated with wild-type HDL.

Cholesteryl ester transfer protein (CETP) mediates the bidirectional exchange of cholesteryl esters (CEs) and triglycerides between HDL and LDL (1)⁠. Animal models along with early clinical studies have demonstrated that the impairment of CETP's functionality is important for the efficient treatment of cardiovascular diseases. Despite the pharmacological interest, CETP's lipid transfer mechanism is poorly understood. Recent cryo-electron microscopy studies suggested that CETP penetrates its N-and C-terminal β-barrel domains into HDL and LDL respectively to form a ternary complex (2)⁠. Further it was proposed that the hydrophobic tunnel of CETP can simultaneously interact with the core of HDL and LDL for continuous lipid exchange. However, the detailed lipid transfer process is still inconclusive. In this study, we employed coarse-grained molecular dynamics simulations to illuminate the lipid transfer mechanism of CETP in HDL-CETP-LDL ternary complex. The extent of penetration of CETP into HDL and LDL in our ternary complex model corroborated well with the experimental findings. Further, the results demonstrated that the ejection of C-terminal plug-in phospholipid (PLC) and subsequently the diffusion of CETP-bound CEs into LDL droplet through PLC opening. A detailed analysis on interactions of PLC pocket lining residues with the discharged lipids revealed residues with significant role in CE transfer. The detailed mechanism of lipid transfer by CETP as explored in this study might help designing future CETP research and subsequent CETP therapeutics.References:1. Tall, A.R. Plasma cholesteryl ester transfer protein. J. Lipid Res. 34: 1255–1274 (1993).2. Zhang, L. et al., Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein. Nat. Chem. Biol. 8: 342–349 (2012).

We investigated the effects of HMG-CoA reductase inhibitors (statins) on the activity and concentration of plasma cholesterol ester transfer protein (CETP) in 30 hypercholesterolemic patients. Patients were divided into three groups according to TaqIB polymorphism of the CETP gene. The activity (158 +/- 23% control, mean +/- SEM) and concentration (4.1 +/- 1.0 mg/l) of plasma CETP were significantly (p < 0.005) higher in the subjects with the B1B1 genotype than B2B2 genotype (106 +/- 25% and 2.5 +/- 1.1 mg/l, respectively). Plasma CETP activity and concentration levels in the B1B2 group were intermediate between those of the B1B1 and B2B2 groups, and significantly (p < 0.05) low compared with the B1B1 group.Both the activity and concentration of plasma CETP were positively correlated with the LDL-cholesterol concentration (r = 0.608, p < 0.0005 and r = 0.552, p < 0.005, respectively). The administration of statins significantly reduced not only the activity (p < 0.01) but also the concentration (p < 0.05) of plasma CETP in hypercholesterolemic patients. Taken together, we confirmed that statins would be effective in increasing HDL levels in Japanese B1B1 carriers, because of a lower concentration of HDL cholesterol and higher level of plasma CETP compared to the other genotypes. The genetic variation in the CETP gene may be one important factor in designing better treatments.

Plasma cholesteryl ester transfer protein (CETP) concentrations were measured in Japanese subjects by an ELISA with two different monoclonal antibodies that were raised against rabbit CETP and cross-reacted against human CETP. Among 63 patients who consecutively underwent coronary angiography, the plasma CETP of 37 patients with luminal stenosis ≥50% in their coronary arteries was not significantly different from that of the 26 patients with luminal stenosis

We studied the effects of simvastatin treatment on plasma cholesterylester transfer protein (CETP) activity and lipid levels in patients with type IIa hypercholesterolemia. We treated 24 patients, 4 men and 20 women aged 49 to 81 years (mean age, 64.5 ± 8.5 years), with simvastatin at a daily dose of 5 mg for 4 weeks. Simvastatin treatment significantly decreased plasma total cholesterol (262 ± 28 mg/dL vs 220 ± 28 mg/dL) and low-density lipoprotein cholesterol (LDL-C)(181 ± 26 mg/dL vs 135 ± 28 mg/dL) and significantly increased high-density lipoprotein cholesterol (HDL-C) (57.2 ± 8.4 mg/dL vs 62.8 ± 10.5 mg/dL. CETP activity significantly decreased after 4 weeks of treatment (11.2 ± 3.8%/10 μL/3 h vs 8.9 ± 3.8% 10 μL/3 h. These results suggest that one of the lipid-lowering effects of simvastatin is due to decreased CETP activity, which results in decreased LDL-C and increased HDL-C concentrations.

ApoA-I-containing lipoproteins exist in plasma in two main forms: one contains only apoA-I (LpA-I) while the other contains both apoA-I and apoA-II (LpA-I/A-II). We characterized structural and functional changes of these lipoproteins in six patients with cholesteryl ester transfer protein (CETP) deficiency. In these patients, the amount of LpA-I and LpA-I/A-II had increased significantly. Sixty-five percent of plasma apoA-I was associated with LpA-I/A-II, which indicated that LpA-I/A-II was predominant. The chemical composition of both LpA-I and LpA-I/A-II was characterized by increased ratios of neutral to polar lipid, compared with findings in normal subjects. Particle sizes of these lipoproteins shifted to larger diameter ranges, as compared to the size seen in normal subjects. Incubation of patients' LpA-I and LpA-I/A-II with CETP markedly corrected the chemical and physical abnormalities in these lipoproteins. Cholesterol-reducing capacities of these lipoproteins from macrophage foam cells were significantly lower than in normal controls. Cholesterol esterification rates in LpA-I, LpA-I/A-II, and plasma were significantly lower in patients than in normal controls. We propose that the structure and function of LpA-I and LpA-I/A-II are severely affected in the presence of CETP deficiency.

Clinical trials using cholesteryl ester transfer protein (CETP) inhibitors to raise high-density lipoprotein cholesterol (HDL-C) concentrations reported an 'off-target' blood pressure (BP) raising effect. We evaluated the relations of baseline plasma CETP activity and longitudinal BP change.One thousand, three hundred and seven Framingham Study participants free of cardiovascular disease attending consecutive examinations 4 years apart (mean age 48 years) had baseline plasma CETP activity related to change in BP over the 4-year interval, adjusting for standard risk factors. Systolic BP increased [median +2 mmHg, 95% confidence interval (CI) -16,+23 mmHg], whereas diastolic BP decreased (median -3 mmHg, 95% CI -15,+11 mmHg). Plasma CETP activity was not related to change in diastolic BP, but was inversely related to change in systolic BP that was borderline significant (P=0.09). On multivariable analyses, plasma CETP activity was inversely related to change in pulse pressure (PP; beta per SD increment= -0.71 mmHg, P=0.005). When dichotomized at the median, plasma CETP activity above the median was associated with a 1 mmHg lower PP on follow-up (P=0.045).Decreasing plasma CETP activity was modestly related to increasing PP on follow-up in our community-based sample, suggesting that inhibition of intrinsic CETP activity itself is likely associated with minimal changes in BP.

This study compares the specificities of selective uptake and transfer mediated by plasma cholesteryl ester transfer protein (CETP) for various species of cholesteryl esters in high density lipoproteins (HDL). [3H]Cholesterol was esterified with a series of variable chain length saturated acids and a series of variably unsaturated 18-carbon acids. These were incorporated into synthetic HDL particles along with 125I-labeled apoA-I as a tracer of HDL particles and [14C]cholesteryl oleate as an internal standard for normalization between preparations. Selective uptake by Y1-BS1 mouse adrenal cortical tumor cells was most extensively studied, but uptake by human HepG2 hepatoma cells and fibroblasts of human, rat, and rabbit origin were also examined. Acyl chain specificities for selective uptake and for CETP-mediated transfer were conversely related; selective uptake by all cell types decreased with increasing acyl chain length and increased with the extent of unsaturation of C18 chains. In contrast, CETP-mediated transfer increased with acyl chain length, and decreased with unsaturation of C18 chains. The specificities of human and rabbit CETP were also compared, and were found to differ little. Associated experiments showed that HDL-associated triglycerides, traced by [3H]glyceryl trioleyl ether, were selectively taken up but at a lesser rate than cholesteryl esters. The mechanism of this uptake appears to be the same as for selective uptake of cholesteryl esters.