Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasmaprotein 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 heteroexchange, trading a triglyceride for a cholesteryl ester or a cholesteryl ester for a triglyceride.
The CETP gene is located on the sixteenth chromosome (16q21).
Protein Fold
The crystal structure of CETP is that of dimer of two TUbular LIPid (TULIP) binding domains.[1][2] Each domain consists of a core of 6 elements: 4 beta-sheets forming an extended superhelix; 2 flanking elements that tend to include some alpha helix. The sheets wrap around the helices to produce a cylinder 6 x 2.5 x 2.5 nm. CETP contains two of these domains that interact head-to-head via an interface made of 6 beta-sheets, 3 from each protomer. The same fold is shared by Bacterial Permeability Inducing proteins (examples: BPIFP1BPIFP2BPIFA3 and BPIFB4), phospholipid transfer protein (PLTP), and long-Palate Lung, and Nasal Epithelium protein (L-PLUNC). The fold is similar to intracellular SMP domains,[3] and originated in bacteria.[4][5][6] The crystal structure of CETP has been obtained with bound CETP inhibitors.[7] However, this has not resolved the doubt over whether CETP function as a lipid tube or shuttle.[8]
Role in disease
Rare mutations leading to reduced function of CETP have been linked to accelerated atherosclerosis.[9] In contrast, a polymorphism (I405V) of the CETP gene leading to lower serum levels has also been linked to exceptional longevity [10] and to metabolic response to nutritional intervention.[11] However, this mutation also increases the prevalence of coronary heart disease in patients with hypertriglyceridemia.[12] The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.[9]
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.[14] 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.[15] 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,[16][17] and, in a trial of a combination of torcetrapib and atorvastatin, an increase in cardiovascular events and mortality.[18]
A compound related to torcetrapib, Dalcetrapib (investigative name JTT-705/R1658), was also studied, but trials have ceased.[19] It increases HDL levels by 30%, as compared to 60% by torcetrapib.[20] Two CETP inhibitors were previously under development. One was Merck's MK-0859 anacetrapib, which in initial studies did not increase blood pressure.[21] In 2017, its development was abandoned by Merck.[22] The other was Eli Lilly's evacetrapib, which failed in Phase 3 trials.
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
↑Qiu X, Mistry A, Ammirati MJ, Chrunyk BA, Clark RW, Cong Y, Culp JS, Danley DE, Freeman TB, Geoghegan KF, Griffor MC, Hawrylik SJ, Hayward CM, Hensley P, Hoth LR, Karam GA, Lira ME, Lloyd DB, McGrath KM, Stutzman-Engwall KJ, Subashi AK, Subashi TA, Thompson JF, Wang IK, Zhao H, Seddon AP (February 2007). "Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules". Nature Structural & Molecular Biology. 14 (2): 106–13. doi:10.1038/nsmb1197. PMID17237796.
↑Alva V, Lupas AN (August 2016). "The TULIP superfamily of eukaryotic lipid-binding proteins as a mediator of lipid sensing and transport". Biochimica et Biophysica Acta. 1861 (8 Pt B): 913–923. doi:10.1016/j.bbalip.2016.01.016. PMID26825693.
↑Gustafsson R, Berntsson RP, Martínez-Carranza M, El Tekle G, Odegrip R, Johnson EA, Stenmark P (November 2017). "Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX-type gene cluster". FEBS Letters. 591 (22): 3781–3792. doi:10.1002/1873-3468.12889. PMID29067689.
↑Lauer ME, Graff-Meyer A, Rufer AC, Maugeais C, von der Mark E, Matile H, D'Arcy B, Magg C, Ringler P, Müller SA, Scherer S, Dernick G, Thoma R, Hennig M, Niesor EJ, Stahlberg H (May 2016). "Cholesteryl ester transfer between lipoproteins does not require a ternary tunnel complex with CETP". Journal of Structural Biology. 194 (2): 191–8. doi:10.1016/j.jsb.2016.02.016. PMID26876146.
↑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. PMID14559957.
↑Darabi M, Abolfathi AA, Noori M, Kazemi A, Ostadrahimi A, Rahimipour A, Darabi M, Ghatrehsamani K (July 2009). "Cholesteryl ester transfer protein I405V polymorphism influences apolipoprotein A-I response to a change in dietary fatty acid composition". Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme. 41 (7): 554–8. doi:10.1055/s-0029-1192034. PMID19242900.
↑Bruce C, Sharp DS, Tall AR (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". Journal of Lipid Research. 39 (5): 1071–8. PMID9610775.
↑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. PMID8018112.
↑Barter PJ, Brewer HB, Chapman MJ, Hennekens CH, Rader DJ, Tall AR (February 2003). "Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis". Arteriosclerosis, Thrombosis, and Vascular Biology. 23 (2): 160–7. doi:10.1161/01.ATV.0000054658.91146.64. PMID12588754.
↑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". The New England Journal of Medicine. 350 (15): 1505–15. doi:10.1056/NEJMoa031766. PMID15071125.
↑Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Lasala GP, Tuzcu EM (March 2007). "Effect of torcetrapib on the progression of coronary atherosclerosis". The New England Journal of Medicine. 356 (13): 1304–16. doi:10.1056/NEJMoa070635. PMID17387129.
↑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 (April 2007). "Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia". The New England Journal of Medicine. 356 (16): 1620–30. doi:10.1056/NEJMoa071359. PMID17387131.
↑El Harchaoui K, van der Steeg WA, Stroes ES, Kastelein JJ (August 2007). "The role of CETP inhibition in dyslipidemia". Current Atherosclerosis Reports. 9 (2): 125–33. doi:10.1007/s11883-007-0008-5. PMID17877921.
↑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. PMID11994249.
Okajima F (March 2002). "[Distribution of sphingosine 1-phosphate in plasma lipoproteins and its role in the regulation of the vascular cell functions]". Tanpakushitsu Kakusan Koso. Protein, Nucleic Acid, Enzyme. 47 (4 Suppl): 480–7. PMID11915346.
Dallinga-Thie GM, Dullaart RP, van Tol A (June 2007). "Concerted actions of cholesteryl ester transfer protein and phospholipid transfer protein in type 2 diabetes: effects of apolipoproteins". Current Opinion in Lipidology. 18 (3): 251–7. doi:10.1097/MOL.0b013e3280e12685. PMID17495597.
