Cholesteryl ester transfer protein: the physiological and molecular characteristics in the pathogenesis of atherosclerosis and Alzheimer’s disease

REVIEW ARTICLE

Cholesteryl ester transfer protein: the physiological and molecular characteristics in the pathogenesis of atherosclerosis and Alzheimer’s disease

Justyna Pawlik 1 , Dorota Wrześniok 1

1. Katedra i Zakład Chemii i Analizy Leków, Wydział Farmaceutyczny z Oddziałem Medycyny Laboratoryjnej w Sosnowcu, Śląski Uniwersytet Medyczny, Katowice, Polska,

Published: 2019-08-23
DOI: 10.5604/01.3001.0013.3673
GICID: 01.3001.0013.3673
Available language versions: en pl
Issue: Postepy Hig Med Dosw 2019; 73 : 387-396

 

Abstract

Cholesteryl ester transfer protein (CETP) is involved in reverse cholesterol transport, mediates the exchange of cholesteryl esters for triglycerides between high-density lipoproteinsand low-density lipoproteins/very low-density lipoproteins. Lipid transfer mechanism by CETP is unknown. Two main models have been proposed for the mechanism of action of CETP: shuttle and tunnel mechanisms. The variants of CETP gene affect activity and level of protein, thus they are associated with lipid profile and risk of many diseases. Some clinical studies reported that polymorphisms of CETP, including TaqIB and I405V, are associated with risk of atherosclerosis and/or Alzheimer’s disease. CETP plays important role an in the metabolism of cholesterol, thus is correlated with pathomechanism of coronary artery disease. Inhibition of CETP can be an effective strategy to improve the lipid profile and reduce risk of cardiovascular diseases. Therefore, new therapeutic strategies to reduce activity of CETP or decrease its level are developed. Effectiveness of following pharmacological methods of modulation of CETP activity was studied: anti-CETP vaccines, antisense oligonucleotide and small molecule inhibitors of CETP. This article presents an overview of the literature on the correlation between cardiovascular diseases and CETP protein/CETP gene. Furthermore, it discusses the impact of CETP on pathogenesis of Alzheimer’s disease.

References

  • 1. Abd El-Aziz T.A., Mohamed R.H., Hagrass H.A.: Increased risk ofpremature coronary artery disease in Egyptians with ABCA1 (R219K),CETP (TaqIB), and LCAT (4886C/T) genes polymorphism. J. Clin. Lipidol.,2014; 8(4): 381–9
    Google Scholar
  • 2. Äijänen T., Koivuniemi A., Javanainen M., Rissanen S., Rog T., VattulainenI.: How anacetrapib inhibits the activity of the cholesterylester transfer protein? Perspective through atomistic simulations.PLoS Comput. Biol., 2014; 10(11): e1003987
    Google Scholar
  • 3. Barkowski R., Frishman W.: HDL Metabolism and CETP inhibition.Cardiology Rev., 2008; 16(3): 154–62
    Google Scholar
  • 4. Boekholdt S.M., Sacks F.M., Jukema J.W., Shepherd J., Freeman D.J.,McMahon A.D., Cambien F., Nicaud V., de Grooth G.J., Talmud P.J.,Humphries S.E., Miller G.J., Eiriksdottir G., Gudnason V., Kauma H.i wsp.: Cholesteryl ester transfer protein TaqIB variant, high-densitylipoprotein cholesterol levels, cardiovascular risk, and efficacy ofpravastatin treatment: individual patient meta-analysis of 13,677subjects. Circulation, 2005; 111(3): 278–87
    Google Scholar
  • 5. Corella D., Carrasco P., Fitó M., Martínez-González M.A., Salas-Salvadó J., Arós F., Lapetra J., Guillén M., Ortega-Azorín C., WarnbergJ., Fiol M., Ruiz-Gutierrez V., Serra-Majem L., Martínez J.A., Ros E.i wsp.: Gene-environment interactions of CETP gene variation ina high cardiovascular risk Mediterranean population. J. Lipid Res.,2010; 51: 2798–2807
    Google Scholar
  • 6. Cyrus C., Vatte C., Al-Nafie A., Chathoth S., Al-Ali R., Al-ShehriA., Akhtar M.S., Almansori M., Al-Muhanna F., Keating B., Al-Ali A.:The impact of common polymorphisms in CETP and ABCA1 geneswith the risk of coronary artery disease in Saudi Arabians. Hum.Genomics, 2016; 10: 8
    Google Scholar
  • 7. Dong B., Singh A.B., Fung C., Kan K., Liu J.: CETP inhibitors downregulatehepatic LDL receptor and PCSK9 expression in vitro andin vivo through a SREBP2 dependent mechanism. Atherosclerosis.2014; 235(2): 449–462
    Google Scholar
  • 8. Ferri N., Corsini A., Sirtori C.R., Ruscica M.: Present therapeuticrole of cholesteryl ester transfer protein inhibitors. Pharmacol.Res., 2018; 128: 29–41
    Google Scholar
  • 9. Ghatreh Samani K., Noori M., Rohbani Nobar M., HashemzadehChaleshtori M., Farrokhi E., Darabi Amin M.: I405V and -629C/A polymorphismsof the cholesteryl ester transfer protein gene in patientswith coronary artery disease. Iran. Biomed. J., 2009; 13: 103–8
    Google Scholar
  • 10. Goodarzynejad H., Boroumand M., Behmanesh M., Ziaee S., JalaliA.: Cholesteryl ester transfer protein gene polymorphism (I405V)and premature coronary artery disease in an Iranian population.Bosn. J. Basic Med. Sci. 2016; 16(2): 114–20
    Google Scholar
  • 11. Greene D.J., Izem L., Morton R.E.: Defective triglyceride biosynthesis in CETP-deficient SW872 cells. J. Lipid Res., 2015; 56(9): 1669–78[12] Gu G.L., Xu X.L., Yang Q.Y., Zeng R.L.: Effect of CETP polymorphism on atorvastatin lipid-regulating effect and clinical prognosis of patients with coronary heart disease. Med. Sci. Monit., 2014; 20: 2824–9
    Google Scholar
  • 13. Gundogdu F., Gurlertop Y., Pirim I., Sevimli S., Dogan H., ArslanS., Aksoy H., Karakelloglu S., Senocak H.: The relationship betweengenetic variations of the cholesteryl ester transfer protein geneand coronary artery disease in Turkish subjects. Eurasian J. Med.2009; 41(1): 32–8
    Google Scholar
  • 14. HPS3/TIMI55–REVEAL Collaborative Group, Bowman L.,Hopewell J.C., Chen F., Wallendszus K., Stevens W., Collins R., WiviottS.D., Cannon C.P., Braunwald E., Sammons E., Landray M.J.: Effectsof anacetrapib in patients with atherosclerotic vascular disease. N.Engl. J. Med., 2017; 377(13): 1217–27
    Google Scholar
  • 15. Ikewaki K., Mabuchi H., Teramoto T., Yamada N., Oikawa S., Sasaki J.,Takata K., Saito Y., Japan CETP Study Group: Association of cholesterylester transfer protein activity and TaqIB polymorphism with lipoproteinvariations in Japanese subjects. Metabolism, 2003; 52(12): 1564–70
    Google Scholar
  • 16. Izaks G.J., van der Knaap A.M., Gansevoort R.T., Navis G., SlaetsJ.P., Dullaart R.P.: Cholesteryl ester transfer protein (CETP) genotypeand cognitive function in persons aged 35 years or older. Neurobiol.Aging, 2012; 33(8): 1851.e7–1851.e16
    Google Scholar
  • 17. Jensen M.K., Mukamal K.J., Overvad K., Rimm E.B.: Alcohol consumption,TaqIB polymorphism of cholesteryl ester transfer protein,high-density lipoprotein cholesterol, and risk of coronary heart diseasein men and women. Eur. Heart J., 2008; 29(1): 104–12
    Google Scholar
  • 18. Kolovou G., Mihas C., Anagnostopoulou K., Kolovou V., GiannakopoulouV., Kostakou P., Stamatelatou M., Mavrogeni S., DegiannisD., Mikhailidis D.P.: Cholesteryl ester transfer protein gene and effectivenessof lipid lowering of atorvastatin. Open Cardiovasc. Med.J., 2010; 4: 297–301
    Google Scholar
  • 19. Kolovou G., Vasiliadis I., Kolovou V., Karakosta A., MavrogeniS., Papadopoulou E., Papamentzelopoulos S., Giannakopoulou V.,Marvaki A., Degiannis D., Bilianou H.: The role of common variantsof the cholesteryl ester transfer protein gene in left main coronaryartery disease. Lipids Health Dis., 2011; 10: 156
    Google Scholar
  • 20. Kosmas C.E., DeJesus E., Rosario D., Vittorio T.J.: CETP inhibition:Past failures and future hopes. Clin. Med. Insights Cardiol.,2016; 10: 37–42
    Google Scholar
  • 21. Lauer M.E., Graff-Meyer A., Rufer A.C., Maugeais C., von der MarkE., Matile H., D‘Arcy B., Magg C., Ringler P., Müller S.A., Scherer S.,Dernick G., Thoma R., Hennig M., Niesor E.J. i wsp.: Cholesteryl estertransfer between lipoproteins does not require a ternary tunnelcomplex with CETP. J. Struct. Biol., 2016; 194(2): 191–8
    Google Scholar
  • 22. Li J., Zhang L., Xie N.Z., Deng B., Lv L.X., Zheng L.Q.: Relationshipbetween the cholesterol ester transfer protein TaqIB polymorphismand the lipid-lowering effect of atorvastatin in patients withcoronary atherosclerotic heart disease. Genet. Mol. Res., 2014; 13(1):2140–8
    Google Scholar
  • 23. Liaw Y.W., Lin C.Y., Lai Y.S., Yang T.C., Wang C.J., Whang-PengJ., Liu L.F., Lin C.P., Nieh S., Lu S.C., Hwang J.: A vaccine targetedat CETP alleviates high fat and high cholesterol diet-induced atherosclerosisand non-alcoholic steatohepatitis in rabbit. PLoS One,2014; 9(12): e111529
    Google Scholar
  • 24. Lira M.E., Loomis A.K., Paciga S.A., Lloyd D.B., Thompson J.F.:Expression of CETP and of splice variants induces the same levelof ER stress despite secretion efficiency differences. J. Lipid Res.,2008; 49: 1955–62
    Google Scholar
  • 25. Mabuchi H., Nohara A., Inazu A.: Cholesteryl ester transfer protein(CETP) deficiency and CETP inhibitors. Mol. Cells, 2014; 37(11):777–84
    Google Scholar
  • 26. Meiner V., Friedlander Y., Milo H., Sharon N., Ben-Avi L., ShpitzenS., Leitersdorf E., Siscovick D.S., Schwartz S.M.: Cholesteryl estertransfer protein (CETP) genetic variation and early onset of nonfatalmyocardial infarction. Ann. Hum. Genet., 2008; 72(Pt 6): 732–41
    Google Scholar
  • 27. Miller N.: CETP inhibitors and cardiovascular disease: Time tothink again. F1000 Res., 2014; 3: 124
    Google Scholar
  • 28. Mirmiran P., Esfandiar Z., Hosseini-Esfahani F., Koochakpoor G.,Daneshpour M.S., Sedaghati-Khayat B., Azizi F.: Genetic variations ofcholesteryl ester transfer protein and diet interactions in relationto lipid profiles and coronary heart disease: a systematic review.Nutr. Metab., 2017; 14: 77
    Google Scholar
  • 29. Mohammadpour A.H., Akhlaghi F.: Future of cholesteryl estertransfer protein (CETP) inhibitors: a pharmacological perspective.Clin. Pharmacokinet., 2013; 52(8): 615–26
    Google Scholar
  • 30. Murphy E.A., Roddey J.C., McEvoy L.K., Holland D., Hagler D.J. Jr,Dale A.M., Brewer J.B., Alzheimer’s Disease Neuroimaging Initiative:CETP polymorphisms associate with brain structure, atrophy rate,and Alzheimer’s disease risk in an APOE-dependent manner. BrainImaging Behav., 2012; 6(1): 16–26
    Google Scholar
  • 31. Nagano M., Yamashita S., Hirano K., Takano M., Maruyama T., Ishihara M., Sagehashi Y., Kujiraoka T., Tanaka K., Hattori H., Sakai N., Nakajima N., Egashira T., Matsuzawa Y.: Molecular mechanisms of cholesteryl ester transfer protein deficiency in Japanese. J. Atheroscler. Thromb., 2004; 11(3): 110–21
    Google Scholar
  • 32. Pachocka L.M., Włodarczyk M., Nowicka G., Kłosiewicz-Latoszek L., Wolańska D., Stolarska I.: Polimorfizm TAQIB genu CETP a stężenie lipidów u pacjentów z nadwagą i otyłością. Rocz. Panstw. Zakl. Hig., 2012; 63(2): 149–54
    Google Scholar
  • 33. Papp A.C., Pinsonneault J.K., Wang D., Newman L.C., Gong Y., Johnson J.A., Pepine C.J., Kumari M., Hingorani A.D., Talmud P.J., Shah S., Humphries S.E., Sadee W.: Cholesteryl ester transfer protein (CETP) polymorphisms affect mRNA splicing, HDL levels, and sex dependent cardiovascular risk. PLoS One, 2012; 7(3): e31930
    Google Scholar
  • 34. Parra E.S., Panzoldo N.B., Kaplan D., de Oliveira H.C., dos Santos J.E., de Carvalho L.S., Sposito A.C., Gidlund M., Nakamura R.T., de Souza Zago V.H., Nakandakare E.R., Quintão E.C., de Faria E.C.: The I405V and Taq1B polymorphisms of the CETP gene differentially affect sub-clinical carotid atherosclerosis. Lipids Health Dis., 2012; 11: 130
    Google Scholar
  • 35. Regieli J.J., Jukema J.W., Grobbee D.E., Kastelein J.J., Kuivenhoven J.A., Zwinderman A.H., van der Graaf Y., Bots M.L., Doevendans P.A.: CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse pharmacogenetic interaction. Eur. Heart J., 2008; 29(22): 2792–9
    Google Scholar
  • 36. Shinkai H.: Cholesteryl ester transfer-protein modulator and inhibitors and their potential for the treatment of cardiovascular diseases. Vasc. Health Risk Manag., 2012; 8: 323–31
    Google Scholar
  • 37. Shrestha S., Wu B.J., Guiney L., Barter P.J., Rye K.A.: Cholesteryl ester transfer protein and its inhibitors. J. Lipid Res. 2018; 59(5): 772–83
    Google Scholar
  • 38. Smart M.C., Dedoussis G., Louizou E., Yannakoulia M., Drenos F., Papoutsakis C., Maniatis N., Humphries S.E., Talmud P.J.: APOE, CETP and LPL genes show strong association with lipid levels in Greek children. Nutr. Metab. Cardiovasc. Dis., 2010; 20(1): 26–33
    Google Scholar
  • 39. Suhy A., Hartmann K., Newman L., Papp A., Toneff T., Hook V., Sadee W.: Genetic variants affecting alternative splicing of human cholesteryl ester transfer protein. Biochem. Biophys. Res. Commun., 2014; 443(4): 1270–4
    Google Scholar
  • 40. Todur S.P., Ashavaid T.F.: Association of CETP and LIPC gene polymorphisms with HDL and LDL sub-fraction levels in a group of Indian subjects: A cross-sectional study. Indian J. Clin. Biochem., 2013; 28(2): 116–23
    Google Scholar
  • 41. Virani S.S., Lee V.V., Brautbar A., Grove M.L., Nambi V., Alam M., Elayda M., Wilson J.M., Willerson J.T., Boerwinkle E., Ballantyne C.M.: Single nucleotide polymorphisms in cholesteryl ester transfer protein gene and recurrent coronary heart disease or mortality in patients with established atherosclerosis. Am. J. Cardiol., 2013; 112(9): 1287–92
    Google Scholar
  • 42. Wang J., Wang L.J., Zhong Y., Gu P., Shao J.Q., Jiang S.S., Gong J.B.: CETP gene polymorphisms and risk of coronary atherosclerosis in a Chinese population. Lipids Health Dis., 2013; 12: 176
    Google Scholar
  • 43. Yu L., Shulman J.M., Chibnik L., Leurgans S., Schneider J.A., De Jager P.L., Bennett D.A.: The CETP I405V polymorphism is associated with an increased risk of Alzheimer’s disease. Aging Cell, 2012; 11(2): 228–33
    Google Scholar
  • 44. Zende P.D., Bankar M.P., Momin A.R., Kamble P.S.: Study of cholesteryl ester transfer protein (CETP) I405v genotype and its association with lipid fractions in myocardial infarction patients: A case control study. J Clin. Diagn. Res., 2014; 8(6): CC01–CC04
    Google Scholar
  • 45. Zhang M., Charles R., Tong H., Zhang L., Patel M., Wang F., Rames M.J., Ren A., Rye K.A., Qiu X., Johns D.G., Charles M.A., Ren G.: HDL surface lipids mediate CETP binding as revealed by electron microscopy and molecular dynamics simulation. Sci. Rep., 2015; 5: 8741
    Google Scholar

Full text

Skip to content