Role of CETP inhibitors in the treatment of dyslipidemia.

PURPOSE OF REVIEW: This review summarizes novel human data on cholesteryl ester-transfer protein (CETP) and atherosclerosis and the possible use of CETP inhibitors in the treatment of dyslipidemia. In addition, it will underline that therapeutic targeting of the high-density lipoprotein (HDL) metabolism entails more than simply observing changes in cholesterol levels of this lipoprotein. RECENT FINDINGS: Two pharmacological small-molecule inhibitors of CETP, JTT-705 and torcetrapib, have recently been shown to effectively raise HDL cholesterol in humans without serious side effects when either used as a monotherapy or combined with statins that lower low-density lipoprotein cholesterol. Importantly, prospective data from the Epic-Norfolk study furthermore indicate that elevated CETP concentration in conjunction with elevated triglyceride levels are associated with increased odds for cardiovascular events. Data from the Diabetic Atherosclerosis Intervention Study furthermore show that elevated CETP concentration is associated with increased progression of coronary atherosclerosis in patients with type 2 diabetes who use fenofibrate. SUMMARY: Long-term studies will have to show whether CETP inhibition decreases the risk of atherosclerotic disease in dyslipidemic patients. Increased CETP activity might be detrimental under hypertriglyceridemic conditions which is of importance when considering that a large proportion of patients at increased risk from coronary artery disease exhibit elevated triglyceride levels. Studies into the effects of CETP inhibition in hypertriglyceridemic patients therefore seem warranted. Awaiting the first data on the effect of CETP inhibition on surrogate endpoints for atherosclerosis, this review furthermore outlines that the complexity of HDL metabolism will necessitate a wide variety of studies on many aspects of this intriguing lipoprotein.

Cholesteryl ester transfer protein concentration is associated with progression of atherosclerosis and response to pravastatin in men with coronary artery disease (REGRESS).

BACKGROUND: The TaqIB polymorphism in the cholesteryl ester transfer protein (CETP) gene is associated with HDL-C, progression of coronary artery disease (CAD) and response to pravastatin treatment in men with angiographically proven CAD (REGRESS). We hypothesized that differences in CETP concentration could explain these associations and now investigated whether CETP concentration is an independent determinant of these parameters. MATERIALS AND METHODS: Plasma CETP concentrations at baseline and after 2 years' treatment with pravastatin or placebo were measured (n=674), and correlations with lipid and angiographic parameters (mean segment- and obstruction-diameter; MSD and MOD), and TaqIB genotype were studied. RESULTS: After segregation into three groups (baseline CETP<1.58, 1.58-2.21, >2.21 mg L(-1)), subjects with the highest CETP had significantly higher baseline total cholesterol, LDL-C and triglycerides (P<0.01), while HDL-C, MSD and MOD were not different among these groups. After 2 years of placebo, the MSD decreased threefold (P<0.001) and the MOD decreased 2.4-fold (P=0.042) more in the highest compared with the lowest CETP quartile. Pravastatin treatment reduced total cholesterol LDL-C and triglycerides significantly more in the highest CETP quartile. Moreover, only in the highest CETP quartile, pravastatin significantly reduced the MSD- (P=0.003) and MOD-decrease (P=0.014) compared with placebo, and, notably, this was independent of baseline lipids and differential lipid changes in these quartiles. Strikingly, baseline associations and treatment responses according to baseline CETP were independent of TaqIB genotype. CONCLUSIONS: High CETP concentration is associated with faster progression of coronary atherosclerosis in men with proven CAD. Second, pravastatin yielded the highest improvement of lipid and angiographic parameters in patients with high baseline CETP independent of baseline lipids, lipid changes and TaqIB genotype, indicating that the plasma CETP level itself is an important determinant of the response to statins.

Estimation of multilocus haplotype effects using weighted penalised log-likelihood: analysis of five sequence variations at the cholesteryl ester transfer protein gene locus.

Direct analyses of haplotype effects can be used to identify those specific combinations of alleles that are associated with a specific phenotype. We introduce a method for direct haplotype analysis that solves two problems that arise when haplotypes are analysed in populations of unrelated subjects. Instead of assigning a single, most likely, haplotype pair to multiple heterozygous subjects, all haplotype pairs compatible with their genotype were determined and the posterior probabilities of these pairs were calculated using Bayes' theorem and estimated haplotype frequencies. For the individual patients, all possible haplotype pairs were included in the statistical analysis using the posterior probabilities as weights, which were re-estimated in an iterative process together with the haplotype effects. The second problem of unstable haplotype effect estimates, due to the numerous haplotypes and the low frequency at which some occur, was solved by assuming that haplotypes sharing the same alleles show a similar effect and that the extent of this similarity relates to the number of alleles shared. These assumptions were incorporated in a weighted log-likelihood model by introducing a penalty, where differences in effects of similar haplotypes were penalised. Using CETP gene haplotypes, consisting of five closely linked polymorphisms, and baseline CETP and HDL-C concentrations from the REGRESS population, we demonstrated that the model resulted in more stable effects than estimates based on unambiguous patients only.

Spatio-temporal expression of a gene encoding a putative RNA-binding protein during the early larval development of the mollusc Patella vulgata.

In the mollusc Patella vulgata a cDNA clone named Esther 32 (E32) was found to be expressed in a specific spatio-temporal pattern. DNA sequence analysis showed that E32 represents a putative RNA-binding protein containing a KH domain. In early trochophore larvae, expression of E32 was found in all cells except the already differentiated trochoblasts and the apical tuft cells. Later on in development, expression was also abolished in the presumptive shell gland and restricted to specific areas, among which were the head and foot anlage. This suggests that E32 is involved in maintaining cells in an undifferentiated state via a post-transcriptional mechanism.

Micromere formation at third cleavage is decisive for trochoblast specification in the embryogenesis of Patella vulgata.

Trochoblasts of the mollusc Patella vulgata differentiate early in development into ciliated cells due to a cell intrinsic developmental capacity. The third cleavage appears to be decisive for their specification. Permanent inhibition of cleavage after the third cleavage, as induced by a continuous incubation with the drug Cytochalasin B, had no effect on trochoblast-specific gene expression later in development. However, permanent inhibition of cleavage before third cleavage abolished trochoblast differentiation including trochoblast-specific gene expression. Inhibition of just the third cleavage itself was sufficient to repress trochoblast-specific gene expression. In contrast, inhibiting the second or fourth cleavage did not effect trochoblast-specific gene expression. Correct formation of micromeres at the third cleavage is required to obtain trochoblast-specific gene expression as was shown in experiments in which the formation of micromeres during third cleavage was suppressed by pressure. In addition, centrifugation before or during the third cleavage disturbs trochoblast-specific gene expression, whereas centrifugation after the third cleavage does not affect trochoblast-specific gene expression. Thus, during the third cleavage a decisive step in the determination of developmental fate of trochoblasts takes place, likely resulting in a segregation of activating and inhibitory determinants. Trochoblast-specific markers in Patella were only expressed in embryos that were division arrested after third cleavage. This suggests that a segregation of differentiation potentials has to take place before trochoblast differentiation markers are expressed. The restriction of differentiation potentials in the cleaving stage embryo is thus required to enable trochoblast-specific gene expression.

Restricted distribution of tetraploid cells in mouse tetraploid<==>diploid chimaeras.

Tetraploid mouse embryos were produced by electrofusion at the 2-cell stage, cultured overnight, and aggregated with normal diploid embryos to produce tetraploid<==>diploid (4n<==>2n) chimaeric conceptuses. At 7 1/2 days the 4n<==>2n chimaeras were usually smaller and developmentally retarded compared to control diploid<==>diploid chimaeras. At 12 1/2 days the 4n<==>2n chimaeras had heavier placentas but there was no significant difference in fetal size. Tetraploid cells showed a restricted tissue distribution at both developmental stages studied: 4n cells were commonly present in both the primitive endoderm and the trophectoderm lineages but they rarely contributed to the primitive ectoderm lineage. The overall similarity in the distribution of tetraploid cells at 7 1/2 and 12 1/2 days implies that whatever causes the restricted tissue distribution operates largely before 7 1/2 days. There was no evidence for excessive embryonic losses of 4n<==>2n chimaeras. So, if the restricted distribution of 4n cells was a result of cell selection, the mechanism is more likely to involve loss of 4n cells from the primitive ectoderm early in development rather than selective death of conceptuses with tetraploid cells in this lineage. Alternatively, 4n cells may be preferentially allocated to the trophectoderm and primitive endoderm rather than the primitive ectoderm layer at the blastocyst stage.