Cholesterylester transfer protein
Cholesteryl ester transfer protein, plasma
| PDB rendering based on 2obd.
| Available structures: 2obd
| External IDs
|| OMIM: 118470 Homologene: 47904
| Molecular Function:
|| • catalytic activity|
• lipid binding
| Biological Process:
|| • lipid metabolic process|
• lipid transport
• steroid metabolic process
• cholesterol metabolic process
| RNA expression pattern
More reference expression data
|| NM_000078 (mRNA)|
|| Chr 16: 55.55 - 55.58 Mb
| Pubmed search
Cholesteryl ester transfer protein (CETP) (also called plasma lipid transfer protein) is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very low density or low density lipoproteins (VLDL or LDL) and exchanges them for cholesteryl esters from high density lipoproteins (and vice versa). Most of the time, however, CETP does a homoexchange- trading a triglyceride for a triglyceride or a cholesteryl ester for a cholesteryl ester.
Additional recommended knowledge
The CETP gene is located on the sixteenth chromosome (16q21).
Role in disease
Rare mutations leading to increased function of CETP have been linked to accelerated atherosclerosis. In contrast, a polymorphism (I405V) of the CETP gene leading to lower serum levels has also been linked to exceptional longevity. However, this mutation also increases the prevalence of coronary heart disease in patients with hypertriglyceridemia. The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.
Elaidic acid—a major component of trans fat—increases CETP activity.
As HDL has a protective function in atherosclerosis and cardiovascular disease, and certain disease states (such as the metabolic syndrome) feature low HDL, pharmacological inhibition of CETP is being studied as a method to improve HDL levels. Specifically, the small molecular agent torcetrapib was shown to increase HDL levels (alone and with a statin) and lower LDL (when co-administered with a statin) in a 2004 study. Studies into cardiovascular endpoints, however, were largely disappointing; while they confirmed the change in lipid levels, most reported an increase in blood pressure, no change in atherosclerosis, and (in a trial of a combination of torcetrapib and atorvastatin) an increase in cardiovascular events and mortality.
A compound related to torcetrapib, going by the investigative name JTT-705/R1658, is undergoing studies. It increases HDL levels by 30% (as compared to 60% by torcetrapib).. Another CETP inhibitor under development is Merck's MK-0859 anacetrapib, which in initial studies has been shown not to increase blood pressure.
- ^ a b Zhong S, Sharp DS, Grove JS, Bruce C, Yano K, Curb JD, Tall AR (Jun 1996). "Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels". J Clin Invest 97 (12): 2917-23. PMID 8675707.
- ^ Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR (Oct 2003). "Unique lipoprotein phenotype and genotype associated with exceptional longevity". JAMA 290 (15): 2030-40. PMID 14559957.
- ^ Bruce C, Sharp DS, Tall AR (May 1998). "". J Lipid Res 39 (5): 1071-8. PMID 9610775.
- ^ Abbey M, Nestel PJ (1994). "Plasma cholesteryl ester transfer protein activity is increased when trans-elaidic acid is substituted for cis-oleic acid in the diet". Atherosclerosis 106 (1): 99–107. doi:10.1016/0021-9150(94)90086-8. PMID 8018112.
- ^ Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR (Feb 2003). "Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis". Arterioscler Thromb Vasc Biol 23 (2): 160-7. PMID 12588754.
- ^ Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ (Apr 2004). "Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol". N Engl J Med 350 (15): 1505-15. PMID 15071125.
- ^ Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Tuzcu EM; ILLUSTRATE Investigators (Mar 2007). "Effect of torcetrapib on the progression of coronary atherosclerosis". N Engl J Med 356 (13): 1304-16. PMID 17387129.
- ^ Kastelein JJ, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ, Revkin JH, Grobbee DE, Riley WA, Shear CL, Duggan WT, Bots ML; RADIANCE 1 Investigators. (Apr 2007). "Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia". N Engl J Med 356 (16): 1620-30. PMID 17387131.
- ^ U.S. Food and Drug Administration (3 December 2006). "Pfizer Stops All Torcetrapib Clinical Trials in Interest of Patient Safety". Press release.
- ^ El Harchaoui K, van der Steeg WA, Stroes ES, Kastelein JJ (Aug 2007). "The role of CETP inhibition in dyslipidemia". Curr Atheroscler Rep 9 (2): 125-33. PMID 17877921.
- ^ de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJ (May 2002). "Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study". Circulation 105 (18): 2159-65. PMID 11994249.
- ^ Reuters. "Merck announces its investigational CETP-Inhibitor, MK-0859, produced positive effects on lipids with no observed blood pressure changes", Reuters, Inc., 4 October 2007. Retrieved on 2007-11-04.
- Okajima F (2002). "[Distribution of sphingosine 1-phosphate in plasma lipoproteins and its role in the regulation of the vascular cell functions]". Tanpakushitsu Kakusan Koso 47 (4 Suppl): 480-7. PMID 11915346.
- Barter PJ, Brewer HB, Chapman MJ, et al. (2003). "Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis.". Arterioscler. Thromb. Vasc. Biol. 23 (2): 160-7. PMID 12588754.
- Dallinga-Thie GM, Dullaart RP, van Tol A (2007). "Concerted actions of cholesteryl ester transfer protein and phospholipid transfer protein in type 2 diabetes: effects of apolipoproteins.". Curr. Opin. Lipidol. 18 (3): 251-7. doi:10.1097/MOL.0b013e3280e12685. PMID 17495597.