Okamoto, H. et al. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature 406, 203-207

Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, JT Inc., Takatsuki, Osaka, Japan.
Nature (Impact Factor: 41.46). 07/2000; 406(6792). DOI: 10.1038/35018119


Cholesteryl ester transfer protein (CETP) is a plasma protein that mediates the exchange of cholesteryl ester in high-density lipoprotein (HDL) for triglyceride in very low density lipoprotein (VLDL). This process decreases the level of anti-atherogenic HDL cholesterol and increases pro-atherogenic VLDL and low density lipoprotein (LDL) cholesterol, so CETP is potentially atherogenic. On the other hand, CETP could also be anti-atherogenic, because it participates in reverse cholesterol transport (transfer of cholesterol from peripheral cells through the plasma to the liver). Because the role of CETP in atherosclerosis remains unclear, we have attempted to develop a potent and specific CETP inhibitor. Here we describe CETP inhibitors that form a disulphide bond with CETP, and present one such inhibitor (JTT-705) that increases HDL cholesterol, decreases non-HDL cholesterol and inhibits the progression of atherosclerosis in rabbits. Our findings indicate that CETP may be atherogenic in vivo and that JTT-705 may be a potential anti-atherogenic drug.

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    • "CETP plays a dual role in regulating atherogenesis. At one point, CETP plays a major role in regulating blood HDL by mediating the transfer of neutral lipids randomly between the lipoprotein cores, such as cholesteryl ester and triglyceride (Okamoto et al., 2000). Low CETP can result in high HDL, which is beneficial for atherosclerosis. "
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    ABSTRACT: Garlic has long been the focus of experimental and clinical attentions due to its promising lipid-lowering effects. Numerous animal studies as well as in vitro ones have demonstrated the hypolipidemic effects of garlic, while clinical trials are highly inconsistent. Based on some double-blind, randomized, placebo-controlled clinical trials which denied the hypolipidemic effects of garlic, some meta-analysis concluded that garlic did not possess beneficial effects for hyperlipidemia. However, we should not ignore the abundant supporting data in the literature. It should be noted that the doses of garlic used in clinical trials were usually far lower than those used in animal studies, which might cover its potential effects. The type of the garlic products may be another important factor responsible for the conflicting outcomes, as different garlic products are composed of different organosulfur compounds. In addition, the biological availability of garlic products is of importance, which was omitted in many studies. Moreover, some studies indicated that different people might have a different response to garlic, and thus garlic may be more beneficial for some specific groups. Collectively, it may be inappropriate to draw a conclusion that garlic does not benefit for hyperlipidemia. Future studies with larger samples are needed to further clarify the effects of garlic used at higher but non-toxic doses on specific groups.
    No preview · Article · Jan 2013 · Critical reviews in food science and nutrition
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    • "Thus, CETP is involved in cholesterol efflux in RCT, and plays a crucial role in regulating HDL-C levels. These effects were also reported to be induced by a CETP inhibitor as well as congenital CETP deficiency [11], [12]. This suggests that inhibitors of CETP may act as anti-atherogenic agents [13]–[15]. "
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    ABSTRACT: Xanthohumol is expected to be a potent anti-atherosclerotic agent due to its inhibition of cholesteryl ester transfer protein (CETP). In this study, we hypothesized that xanthohumol prevents atherosclerosis in vivo and used CETP-transgenic mice (CETP-Tg mice) to evaluate xanthohumol as a functional agent. Two strains of mice, CETP-Tg and C57BL/6N (wild-type), were fed a high cholesterol diet with or without 0.05% (w/w) xanthohumol ad libitum for 18 weeks. In CETP-Tg mice, xanthohumol significantly decreased accumulated cholesterol in the aortic arch and increased HDL cholesterol (HDL-C) when compared to the control group (without xanthohumol). Xanthohumol had no significant effect in wild-type mice. CETP activity was significantly decreased after xanthohumol addition in CETP-Tg mice compared with the control group and it inversely correlated with HDL-C (%) (P<0.05). Furthermore, apolipoprotein E (apoE) was enriched in serum and the HDL-fraction in CETP-Tg mice after xanthohumol addition, suggesting that xanthohumol ameliorates reverse cholesterol transport via apoE-rich HDL resulting from CETP inhibition. Our results suggest xanthohumol prevents cholesterol accumulation in atherogenic regions by HDL-C metabolism via CETP inhibition leading to apoE enhancement.
    Full-text · Article · Nov 2012 · PLoS ONE
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    • "Dalcetrapib (JTT-705) is the first small molecule that has succeeded in regulating CETP and demonstrating an anti-atherogenic effect in vivo.23 Dalcetrapib is a benzenethiol derivative (Figure 2) that inhibits the CETP-mediated transfer of CE from HDL to apoB-containing lipoproteins in human plasma at an IC50 of 9 μM. "
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    ABSTRACT: Elevated low-density lipoprotein (LDL) cholesterol and lowered high-density lipoprotein (HDL) cholesterol are important risk factors for cardiovascular disease. Accordingly, raising HDL cholesterol induced by cholesteryl ester transfer protein (CETP) inhibition is an attractive approach for reducing the residual risk of cardiovascular events that persist in many patients receiving low-density LDL cholesterol-lowering therapy with statins. The development of torcetrapib, a CETP inhibitor, was terminated due to its adverse cardiovascular effects. These adverse effects did not influence the mechanism of CETP inhibition, but affected the molecule itself. Therefore a CETP modulator, dalcetrapib, and a CETP inhibitor, anacetrapib, are in Phase III of clinical trials to evaluate their effects on cardiovascular outcomes. In the dal-VESSEL (dalcetrapib Phase IIb endothelial function study) and the dal-PLAQUE (safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging) clinical studies, dalcetrapib reduced CETP activity by 50% and increased HDL cholesterol levels by 31% without changing LDL cholesterol levels. Moreover, dalcetrapib was associated with a reduction in carotid vessel-wall inflammation at 6 months, as well as a reduced vessel-wall area at 24 months compared with the placebo. In the DEFINE (determining the efficacy and tolerability of CETP inhibition with anacetrapib) clinical study, anacetrapib increased HDL cholesterol levels by 138% and decreased LDL cholesterol levels by 36%. In contrast with torcetrapib, anacetrapib had no adverse cardiovascular effects. The potential of dalcetrapib and anacetrapib in the treatment of cardiovascular diseases will be revealed by two large-scale clinical trials, the dal-OUTCOMES (efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome) study and the REVEAL (randomized evaluation of the effects of anacetrapib through lipid modification, a large-scale, randomized placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease) study. The dal-OUTCOMES study is testing whether dalcetrapib can reduce cardiovascular events and the REVEAL study is testing whether anacetrapib can reduce cardiovascular events. These reports are expected to be released by 2013 and 2017, respectively.
    Full-text · Article · May 2012 · Vascular Health and Risk Management
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