Cholesteryl ester transfer protein explained

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 Chylomicrons 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.

Genetics

The CETP gene is located on chromosome 16 (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: BPIFP1 BPIFP2 BPIFA3 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]

Elaidic acid, a major component of trans fat, increases CETP activity.[13]

Pharmacology

See also: CETP inhibitor. 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.

Further reading

Notes and References

  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 . Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules . Nature Structural & Molecular Biology . 14 . 2 . 106–13 . February 2007 . 17237796 . 10.1038/nsmb1197 . 30939809 .
  2. Alva V, Lupas AN . 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 . August 2016 . 26825693 . 10.1016/j.bbalip.2016.01.016 .
  3. Reinisch KM, De Camilli P . SMP-domain proteins at membrane contact sites: Structure and function . Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids . 1861 . 8 Pt B . 924–927 . August 2016 . 26686281 . 4902782 . 10.1016/j.bbalip.2015.12.003 .
  4. Wong LH, Levine TP . Tubular lipid binding proteins (TULIPs) growing everywhere . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1864 . 9 . 1439–1449 . September 2017 . 28554774 . 5507252 . 10.1016/j.bbamcr.2017.05.019 .
  5. Lam KH, Qi R, Liu S, Kroh A, Yao G, Perry K, Rummel A, Jin R . The hypothetical protein P47 of Clostridium botulinum E1 strain Beluga has a structural topology similar to bactericidal/permeability-increasing protein . Toxicon . 147 . 19–26 . June 2018 . 29042313 . 5902665 . 10.1016/j.toxicon.2017.10.012 .
  6. Gustafsson R, Berntsson RP, Martínez-Carranza M, El Tekle G, Odegrip R, Johnson EA, Stenmark P . Crystal structures of OrfX2 and P47 from a Botulinum neurotoxin OrfX-type gene cluster . FEBS Letters . 591 . 22 . 3781–3792 . November 2017 . 29067689 . 10.1002/1873-3468.12889 . free .
  7. Liu S, Mistry A, Reynolds JM, Lloyd DB, Griffor MC, Perry DA, Ruggeri RB, Clark RW, Qiu X . Crystal structures of cholesteryl ester transfer protein in complex with inhibitors . The Journal of Biological Chemistry . 287 . 44 . 37321–9 . October 2012 . 22961980 . 3481329 . 10.1074/jbc.M112.380063 . free .
  8. 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 . Cholesteryl ester transfer between lipoproteins does not require a ternary tunnel complex with CETP . Journal of Structural Biology . 194 . 2 . 191–8 . May 2016 . 26876146 . 10.1016/j.jsb.2016.02.016 . free .
  9. Zhong S, Sharp DS, Grove JS, Bruce C, Yano K, Curb JD, Tall AR . Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels . The Journal of Clinical Investigation . 97 . 12 . 2917–23 . June 1996 . 8675707 . 507389 . 10.1172/JCI118751 .
  10. Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, Lipton R, Cheng S, Shuldiner AR . Unique lipoprotein phenotype and genotype associated with exceptional longevity . JAMA . 290 . 15 . 2030–40 . October 2003 . 14559957 . 10.1001/jama.290.15.2030 . 22792639 .
  11. Darabi M, Abolfathi AA, Noori M, Kazemi A, Ostadrahimi A, Rahimipour A, Darabi M, Ghatrehsamani K . 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 . July 2009 . 19242900 . 10.1055/s-0029-1192034 . 260169359 .
  12. Bruce C, Sharp DS, Tall AR . 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 . May 1998 . 10.1016/S0022-2275(20)33876-1 . 9610775 . free .
  13. Abbey M, Nestel PJ . 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 . March 1994 . 8018112 . 10.1016/0021-9150(94)90086-8 .
  14. Barter PJ, Brewer HB, Chapman MJ, Hennekens CH, Rader DJ, Tall AR . Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis . Arteriosclerosis, Thrombosis, and Vascular Biology . 23 . 2 . 160–7 . February 2003 . 12588754 . 10.1161/01.ATV.0000054658.91146.64 . free .
  15. Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ . Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol . The New England Journal of Medicine . 350 . 15 . 1505–15 . April 2004 . 15071125 . 10.1056/NEJMoa031766 . free .
  16. Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Lasala GP, Tuzcu EM . Effect of torcetrapib on the progression of coronary atherosclerosis . The New England Journal of Medicine . 356 . 13 . 1304–16 . March 2007 . 17387129 . 10.1056/NEJMoa070635 . Illustrate . Investigators . free .
  17. 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 . Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia . The New England Journal of Medicine . 356 . 16 . 1620–30 . April 2007 . 17387131 . 10.1056/NEJMoa071359 . free .
  18. Pfizer Stops All Torcetrapib Clinical Trials in Interest of Patient Safety . U.S. Food and Drug Administration . 2006-12-03 .
  19. El Harchaoui K, van der Steeg WA, Stroes ES, Kastelein JJ . The role of CETP inhibition in dyslipidemia . Current Atherosclerosis Reports . 9 . 2 . 125–33 . August 2007 . 17877921 . 10.1007/s11883-007-0008-5 . free .
  20. de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJ . 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 . May 2002 . 11994249 . 10.1161/01.CIR.0000015857.31889.7B . free .
  21. News: Reuters. Merck announces its investigational CETP-Inhibitor, MK-0859, produced positive effects on lipids with no observed blood pressure changes . Reuters, Inc. . 2007-10-04 . 26 November 2013.
  22. News: Merck says will not seek approval of cholesterol treatment. 18 October 2017. Reuters. 2017.

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