Structural and biophysical insight into cholesteryl ester-transfer protein

2011 ◽  
Vol 39 (4) ◽  
pp. 1000-1005 ◽  
Author(s):  
Justin Hall ◽  
Xiayang Qiu
Keyword(s):  
Cholesteryl Ester ◽  
Cholesteryl Ester Transfer Protein ◽  
Low Density Lipoprotein ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Low Density ◽  
Potential Treatment ◽  
Lipid Transfer ◽  
Transfer Protein ◽  
Insight Into

CETP (cholesteryl ester-transfer protein) is essential for neutral lipid transfer between HDL (high-density lipoprotein) and LDL (low-density lipoprotein) and plays a critical role in the reverse cholesterol transfer pathway. In clinical trials, CETP inhibitors increase HDL levels and reduce LDL levels, and therefore may be used as a potential treatment for atherosclerosis. In this review, we cover the analysis of CETP structure and provide insights into CETP-mediated lipid transfer based on a collection of structural and biophysical data.

scholarly journals Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia

2002 ◽  
Vol 103 (6) ◽  
pp. 587-594 ◽  
Author(s):  
Zhiping HUANG ◽  
Akihiro INAZU ◽  
Atsushi NOHARA ◽  
Toshinori HIGASHIKATA ◽  
Hiroshi MABUCHI
Keyword(s):  
Cholesteryl Ester ◽  
Cholesteryl Ester Transfer Protein ◽  
Dose Group ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
High Dose Group ◽  
Control Group ◽  
High Dose ◽  
Low Density ◽  
Transfer Protein

Cholesteryl ester transfer protein (CETP) is a major determinant of plasma levels of high-density lipoprotein-cholesterol (HDL-C) in humans. The anti-atherogenic effect of lowering CETP levels is dependent not only on HDL-C levels but also on a metabolic background of increased low-density lipoprotein or very-low-density lipoprotein. Here we investigated the effects of JTT-705, a chemical inhibitor of CETP, on the development of atherosclerosis in Japanese white rabbits fed on a high cholesterol diet. After 4 weeks on a diet of 0.25% cholesterol-containing chow, 100mg/kg (low dose) or 300mg/kg (high dose) JTT-705 was given, and the animals were monitored at weeks 0, 4, 8 and 12. Aortic atherosclerotic lesions were determined at the end of this period. JTT-705 induced a significant increase in HDL-C in the high-dose group [from 21±3 to 50±7mg/dl (mean±S.E.M.); P<0.0001] compared with the control group (from 21±2 to 27±2mg/dl). The atheromatous area was 60±9% in the high-dose group and 58±9% in the control group. Moreover, correlation analysis showed that triacylglycerol and non-HDL-C levels had a direct relationship with the development of atherosclerosis, but CETP activity and HDL-C levels did not. Thus the CETP inhibitor JTT-705 alone did not have an anti-atherogenic effect in our rabbit model, of severe hypercholesterolaemia suggesting a relatively minor effect of HDL-elevating therapy as compared with decreases in non-HDL-C (or triacylglycerol) levels in patients with severe hypercholesterolaemia, such as familial hypercholesterolaemia.

scholarly journals Bexarotene Induces Dyslipidemia by Increased Very Low-Density Lipoprotein Production and Cholesteryl Ester Transfer Protein-Mediated Reduction of High-Density Lipoprotein

Endocrinology ◽  
2009 ◽  
Vol 150 (5) ◽  
pp. 2368-2375 ◽  
Author(s):  
Jitske de Vries-van der Weij ◽  
Willeke de Haan ◽  
Lihui Hu ◽  
Maarten Kuif ◽  
H. Ling D. W. Oei ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
High Density Lipoprotein ◽  
Cholesteryl Ester ◽  
Cholesteryl Ester Transfer Protein ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Differentiated Thyroid Carcinoma ◽  
Very Low Density Lipoprotein ◽  
Low Density ◽  
Transfer Protein

A common dose-limiting side effect of treatment with the retinoid X receptor agonist bexarotene is dyslipidemia. We evaluated the effects of bexarotene on plasma lipid metabolism in patients with metastatic differentiated thyroid carcinoma and investigated the underlying mechanism(s) in apolipoprotein (APO) E*3-Leiden mice without (E3L) and with human cholesteryl ester transfer protein (CETP; E3L.CETP). To this end, 10 patients with metastatic differentiated thyroid carcinoma were treated with bexarotene (300 mg/d) for 6 wk. Bexarotene increased plasma triglyceride (TG; +150%), primarily associated with very low-density lipoprotein (VLDL), and raised plasma total cholesterol (+50%). However, whereas bexarotene increased VLDL-cholesterol (C) and low-density lipoprotein (LDL)-C (+63%), it decreased high-density lipoprotein (HDL)-C (−30%) and tended to decrease apoAI (−18%) concomitant with an increase in endogenous CETP activity (+44%). To evaluate the cause of the bexarotene-induced hypertriglyceridemia and the role of CETP in the bexarotene-induced shift in cholesterol distribution, E3L and E3L.CETP mice were treated with bexarotene through dietary supplementation [0.03% (wt/wt)]. Bexarotene increased VLDL-associated TG in both E3L (+47%) and E3L.CETP (+29%) mice by increasing VLDL-TG production (+68%). Bexarotene did not affect the total cholesterol levels or distribution in E3L mice but increased VLDL-C (+11%) and decreased HDL-C (−56%) as well as apoAI (−31%) in E3L.CETP mice, concomitant with increased endogenous CETP activity (+41%). This increased CETP activity by bexarotene-treatment is likely due to the increase in VLDL-TG, a CETP substrate that drives CETP activity. In conclusion, bexarotene causes combined dyslipidemia as reflected by increased TG, VLDL-C, and LDL-C and decreased HDL-C, which is the result of an increased VLDL-TG production that causes an increase of the endogenous CETP activity.

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