Cholesterylester transfer protein
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 (VLDL) or low-density lipoproteins (LDL) and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), 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] and to metabolic response to nutritional intervention.[3] However, this mutation also increases the prevalence of coronary heart disease in patients with hypertriglyceridemia.[4] 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.[5]
Pharmacology
As HDL can alleviate atherosclerosis and other cardiovascular diseases, and certain disease states such as the metabolic syndrome feature low HDL, pharmacological inhibition of CETP is being studied as a method of improving HDL levels.[6] To be specific, in a 2004 study, 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.[7] 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,[8][9] and, in a trial of a combination of torcetrapib and atorvastatin, an increase in cardiovascular events and mortality.[10]
A compound related to torcetrapib, Dalcetrapib (investigative name JTT-705/R1658), is also being studied.[11] It increases HDL levels by 30%, as compared to 60% by torcetrapib.[12] Another CETP inhibitor under development is Merck's MK-0859 anacetrapib, which in initial studies is not shown to increase blood pressure.[13]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [14]
References
- ^ a b Zhong S, Sharp DS, Grove JS, Bruce C, Yano K, Curb JD, Tall AR (June 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. doi:10.1172/JCI118751. ISSN 0021-9738. PMC 507389. PMID 8675707. http://www.jci.org/cgi/content/full/97/12/2917.
- ^ Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR (October 2003). "Unique lipoprotein phenotype and genotype associated with exceptional longevity". JAMA 290 (15): 2030–40. doi:10.1001/jama.290.15.2030. ISSN 0098-7484. PMID 14559957. http://jama.ama-assn.org/cgi/content/full/290/15/2030.
- ^ Darabi M, Abolfathi AA, Noori M, Kazemi A, Ostadrahimi A, Rahimipour A et al. (2009). "Cholesteryl ester transfer protein I405V polymorphism influences apolipoprotein A-I response to a change in dietary fatty acid composition". Horm Metab Res 41 (7): 554–8. doi:10.1055/s-0029-1192034. PMID 19242900.
- ^ Bruce C, Sharp DS, Tall AR (1 May 1998). "Relationship of HDL and coronary heart disease to a common amino acid polymorphism in the cholesteryl ester transfer protein in men with and without hypertriglyceridemia". J Lipid Res 39 (5): 1071–8. ISSN 0022-2275. PMID 9610775. http://www.jlr.org/cgi/content/full/39/5/1071.
- ^ Abbey M, Nestel PJ (March 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. ISSN 0021-9150. PMID 8018112.
- ^ Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR (February 2003). "Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis". Arterioscler Thromb Vasc Biol 23 (2): 160–7. doi:10.1161/01.ATV.0000054658.91146.64. ISSN 1079-5642. PMID 12588754. http://atvb.ahajournals.org/cgi/content/full/23/2/160.
- ^ Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ (April 2004). "Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol". N Engl J Med 350 (15): 1505–15. doi:10.1056/NEJMoa031766. ISSN 0028-4793. PMID 15071125. http://content.nejm.org/cgi/content/full/350/15/1505.
- ^ Nissen Se, Tardif JC; Investigators, Illustrate; Nicholls, Stephen J.; Revkin, James H.; Shear, Charles L.; Duggan, William T.; Ruzyllo, Witold; Bachinsky, William B. et al. (March 2007). "Effect of torcetrapib on the progression of coronary atherosclerosis". N Engl J Med 356 (13): 1304–16. doi:10.1056/NEJMoa070635. ISSN 0028-4793. PMID 17387129. http://content.nejm.org/cgi/content/full/356/13/1304.
- ^ Kastelein Jj, van Leuven SI, Investigators; Bots; Radiance 1, Leslie; Evans, Greg W.; Kuivenhoven, Jan A.; Barter, Philip J.; Revkin, James H.; Grobbee, Diederick E. et al. (April 2007). "Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia" (abstract). N Engl J Med 356 (16): 1620–30. doi:10.1056/NEJMoa071359. ISSN 0028-4793. PMID 17387131. http://content.nejm.org/cgi/content/abstract/356/16/1620.
- ^ "Pfizer Stops All Torcetrapib Clinical Trials in Interest of Patient Safety" (Press release). U.S. Food and Drug Administration. 2006-12-03. http://www.fda.gov/bbs/topics/news/2006/new01514.html.
- ^ El Harchaoui K, van der Steeg WA, Stroes ES, Kastelein JJ (August 2007). "The role of CETP inhibition in dyslipidemia". Curr Atheroscler Rep 9 (2): 125–33. doi:10.1007/s11883-007-0008-5. ISSN 1523-3804. 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. doi:10.1161/01.CIR.0000015857.31889.7B. ISSN 0009-7322. PMID 11994249. http://circ.ahajournals.org/cgi/content/full/circulationaha;105/18/2159.
- ^ Reuters (2007-10-04). "Merck announces its investigational CETP-Inhibitor, MK-0859, produced positive effects on lipids with no observed blood pressure changes". Reuters, Inc.. http://www.reuters.com/article/inPlayBriefing/idUSIN20071004163052MRK20071004. Retrieved 2007-11-04.
- ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430". http://www.wikipathways.org/index.php/Pathway:WP430.
Further reading
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PDB gallery
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2obd: Crystal Structure of Cholesteryl Ester Transfer Protein
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External links
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| Proteoglycans |
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mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m
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k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon
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m(A16/C10),i(k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)
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biochemical families: prot · nucl · carb (glpr, alco, glys) · lipd (fata/i, phld, strd, gllp, eico) · amac/i · ncbs/i · ttpy/i
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B proteins: BY STRUCTURE: membrane, globular (en, ca, an), fibrous
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| Apolipoproteins |
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| Lipoproteins |
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| Extracellular enzymes |
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| Lipid transfer proteins |
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| ATP-binding cassette transporter |
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mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m
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k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon
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m(A16/C10),i(k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)
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