Cholesteryl ester transfer protein (CETP), also calledplasma lipid transfer protein, is aplasmaprotein that facilitates the transport ofcholesteryl esters andtriglycerides between thelipoproteins. It collects triglycerides fromvery-low-density lipoproteins (VLDL) orchylomicrons and exchanges them for cholesteryl esters fromhigh-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.
Thecrystal structure of CETP is that ofdimer of twoTUbular LIPid (TULIP) binding domains.[3][4] Each domain consists of a core of 6 elements: 4beta-sheets forming an extended superhelix; 2 flanking elements that tend to include somealpha 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 6beta-sheets, 3 from eachprotomer. The same fold is shared by Bacterial Permeability Inducing proteins (examples:BPIFP1BPIFP2BPIFA3 andBPIFB4), phospholipid transfer protein (PLTP), and long-Palate Lung, and Nasal Epithelium protein(L-PLUNC). The fold is similar to intracellular SMP domains,[5] and originated in bacteria.[6][7][8] The crystal structure of CETP has been obtained with boundCETP inhibitors.[9] However, this has not resolved the doubt over whether CETP function as a lipid tube or shuttle.[10]
Rare mutations leading to reduced function of CETP have been linked to acceleratedatherosclerosis.[11] In contrast, a polymorphism (I405V) of theCETP gene leading to lower serum levels has also been linked to exceptional longevity[12] and to metabolic response to nutritional intervention.[13] However, this mutation also increases the prevalence ofcoronary heart disease in patients withhypertriglyceridemia.[14] The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.[11]
AsHDL can alleviate atherosclerosis and othercardiovascular diseases, and certain disease states such as themetabolic syndrome feature low HDL, pharmacological inhibition of CETP is being studied as a method of improving HDL levels.[16] To be specific, in a 2004 study, the small molecular agenttorcetrapib was shown to increase HDL levels, alone and with astatin, and lower LDL when co-administered with a statin.[17] Studies into cardiovascular endpoints, however, were largely disappointing. While they confirmed the change inlipid levels, most reported an increase inblood pressure, no change in atherosclerosis,[18][19] and, in a trial of a combination of torcetrapib andatorvastatin, an increase in cardiovascular events and mortality.[20]
A compound related to torcetrapib,Dalcetrapib (investigative name JTT-705/R1658), was also studied, but trials have ceased.[21] It increases HDL levels by 30%, as compared to 60% by torcetrapib.[22] Two CETP inhibitors were previously under development. One was Merck's MK-0859anacetrapib, which in initial studies did not increase blood pressure.[23] In 2017, its development was abandoned byMerck.[24] The other was Eli Lilly's evacetrapib, which failed in Phase 3 trials.
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.S2CID30939809.
^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 (BBA) - Molecular and Cell Biology of Lipids.1861 (8 Pt B):913–923.doi:10.1016/j.bbalip.2016.01.016.PMID26825693.
^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.S2CID22792639.
^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.41 (7):554–8.doi:10.1055/s-0029-1192034.PMID19242900.S2CID260169359.
^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.
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.S2CID20012553.
