Cholesterylester transfer protein
| Cholesteryl ester transfer protein, plasma | |||||||||
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 PDB rendering based on 2obd. | |||||||||
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| Symbols | CETP ; | ||||||||
| External IDs | Template:OMIM5 HomoloGene: 47904 | ||||||||
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| Species | Human | Mouse | |||||||
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| RefSeq (protein) | n/a | n/a | |||||||
| Location (UCSC) | n/a | n/a | |||||||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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.
Genetics
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.[1] In contrast, a polymorphism (I405V) of the CETP gene leading to lower serum levels has also been linked to exceptional longevity.[2] However, this mutation also increases the prevalence of coronary heart disease in patients with hypertriglyceridemia.[3] The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.[1]
Elaidic acid—a major component of trans fat—increases CETP activity.[4]
Pharmacology
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.[5] 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.[6] 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,[7][8] and (in a trial of a combination of torcetrapib and atorvastatin) an increase in cardiovascular events and mortality.[9]
A compound related to torcetrapib, going by the investigative name JTT-705/R1658, is undergoing studies.[10] It increases HDL levels by 30% (as compared to 60% by torcetrapib).[11]. Another CETP inhibitor under development is Merck's MK-0859 anacetrapib, which in initial studies has been shown not to increase blood pressure.[12]
References
- ↑ 1.0 1.1 Zhong S, Sharp DS, Grove JS, Bruce C, Yano K, Curb JD, Tall AR (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. Unknown parameter
|month=ignored (help) - ↑ Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR (2003). "Unique lipoprotein phenotype and genotype associated with exceptional longevity". JAMA. 290 (15): 2030–40. PMID 14559957. Unknown parameter
|month=ignored (help) - ↑ Bruce C, Sharp DS, Tall AR (1998). J Lipid Res. 39 (5): 1071–8. PMID 9610775 http://www.jlr.org/cgi/content/full/39/5/1071. Unknown parameter
|month=ignored (help); Missing or empty|title=(help) - ↑ 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 (2003). "Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis". Arterioscler Thromb Vasc Biol. 23 (2): 160–7. PMID 12588754. Unknown parameter
|month=ignored (help) - ↑ Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ (2004). "Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol". N Engl J Med. 350 (15): 1505–15. PMID 15071125. Unknown parameter
|month=ignored (help) - ↑ Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Tuzcu EM; ILLUSTRATE Investigators (2007). "Effect of torcetrapib on the progression of coronary atherosclerosis". N Engl J Med. 356 (13): 1304–16. PMID 17387129. Unknown parameter
|month=ignored (help) - ↑ 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. (2007). "Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia". N Engl J Med. 356 (16): 1620–30. PMID 17387131. Unknown parameter
|month=ignored (help) - ↑ "Pfizer Stops All Torcetrapib Clinical Trials in Interest of Patient Safety" (Press release). U.S. Food and Drug Administration. 3 December 2006.
- ↑ El Harchaoui K, van der Steeg WA, Stroes ES, Kastelein JJ (2007). "The role of CETP inhibition in dyslipidemia". Curr Atheroscler Rep. 9 (2): 125–33. PMID 17877921. Unknown parameter
|month=ignored (help) - ↑ de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJ (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. Unknown parameter
|month=ignored (help) - ↑ Reuters (4 October 2007). "Merck announces its investigational CETP-Inhibitor, MK-0859, produced positive effects on lipids with no observed blood pressure changes". Reuters, Inc. Retrieved 2007-11-04.
Further reading
- 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.
External links
- Cholesterol+ester+transfer+proteins at the US National Library of Medicine Medical Subject Headings (MeSH)