Re-evaluation of cholesteryl ester transfer protein function in atherosclerosis based upon genetics and pharmacological manipulation

Current Opinion in Lipidology

Volumn 27, Issue 5, 2016, Pages 459-472

  Yamashita, Shizuya ^a,b   Matsuzawa, Yuji ^a  

^a OSAKA UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^b Rinku General Medical Center   (Japan)

Author keywords

Apolipoprotein a I; Cholesteryl ester transfer protein deficiency; Cholesteryl ester transfer protein inhibitors; Coronary artery disease; HDL cholesterol; Reverse cholesterol transport

Indexed keywords

ANACETRAPIB; APOLIPOPROTEIN A1; CHOLESTEROL ESTER TRANSFER PROTEIN; CHOLESTEROL ESTER TRANSFER PROTEIN INHIBITOR; DALCETRAPIB; EVACETRAPIB; HIGH DENSITY LIPOPROTEIN; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN; LOW DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN RECEPTOR; PROBUCOL; SCAVENGER RECEPTOR BI; TORCETRAPIB; LIPOPROTEIN;

ATHEROGENESIS; ATHEROSCLEROSIS; CHOLESTEROL TRANSPORT; CLINICAL TRIAL (TOPIC); CORONARY ARTERY ATHEROSCLEROSIS; DRUG EFFECT; DRUG TARGETING; GENETIC ANALYSIS; HUMAN; HUMAN GENETICS; HYPERALPHALIPOPROTEINEMIA; LIPOPROTEIN DEFICIENCY; LIPOPROTEIN METABOLISM; META ANALYSIS (TOPIC); NONHUMAN; PRIORITY JOURNAL; PROTEIN DEFICIENCY; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; XANTHOMA; ANIMAL; ANTAGONISTS AND INHIBITORS; BLOOD; DEFICIENCY; DISORDERS OF LIPID AND LIPOPROTEIN METABOLISM; GENETICS; METABOLISM;

ANIMALS; ATHEROSCLEROSIS; CHOLESTEROL ESTER TRANSFER PROTEINS; CLINICAL TRIALS AS TOPIC; HUMANS; LIPID METABOLISM, INBORN ERRORS; LIPOPROTEINS;

EID: 84979715878     PISSN: 09579672     EISSN: 14736535     Source Type: Journal    
DOI: 10.1097/MOL.0000000000000332     Document Type: Review

References (130)

1. Rosenson RS, Brewer HB Jr, Ansell BJ, et al. Dysfunctional HDL and atherosclerotic cardiovascular disease. Nat Rev Cardiol 2016; 13:48-60.
2. Khera AV, Cuchel M, de la Llera-Moya M, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011; 364:127-135.
3. Rohatgi A, Khera A, Berry JD, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med 2014; 371:2383-2393.
4. Shah AS, Tan L, Long JL, et al. Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond. J Lipid Res 2013; 54:2575-2585.
5. van Capelleveen JC, Brewer HB, Kastelein JJ, et al. Novel therapies focused on the high-density lipoprotein particle. Circ Res 2014; 114:193-204.
6. Matsuzawa Y, Yamashita S, Kameda K, et al. Marked hyper-HDL2-cholesterolemia associated with premature corneal opacity. A case report. Atherosclerosis 1984; 53:207-212.
7. Hirano K, Yamashita S, Nakajima N, et al. Genetic cholesteryl ester transfer protein deficiency is extremely frequent in the Omagari area of Japan. Marked hyperalphalipoproteinemia caused by CETP gene mutation is not associated with longevity. Arterioscler Thromb Vasc Biol 1997; 17:1053-1059.
8. Yamashita S, Matsuzawa Y, Okazaki M, et al. Small polydisperse low density lipoproteins in familial hyperalphalipoproteinemia with complete deficiency of cholesteryl ester transfer activity. Atherosclerosis 1988; 70:7-12.
9. Sakai N, Yamashita S, Hirano K, et al. Decreased affinity of low density lipoprotein (LDL) particles for LDL receptors in patients with cholesteryl ester transfer protein deficiency. Eur J Clin Invest 1995; 25:332-339.
10. Ishigami M, Yamashita S, Sakai N, et al. Large and cholesteryl ester-rich highdensity lipoproteins in cholesteryl ester transfer protein (CETP) deficiency cannot protect macrophages from cholesterol accumulation induced by acetylated low-density lipoproteins. J Biochem 1994; 116:257-262.
11. Fielding CJ, Havel RJ. Cholesteryl ester transfer protein: friend or foe? J Clin Invest 1996; 97:2687-2688.
12. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357:2109-2122.
13. Kingwell BA, Chapman MJ, Kontush A, et al. HDL-Targeted therapies: progress, failures and future. Nat Rev Drug Discov 2014; 13:445-464.
14. Rader DJ, de Goma EM. Future of cholesteryl ester transfer protein inhibitors. Ann Rev Med 2014; 65:385-403.
15. Toth PP, Barylski M, Nikolic D, et al. Should low high-density lipoprotein cholesterol (HDL-C) be treated? Best Pract Res Clin Endocrinol Metab 2014; 28:353-368.
16. Sirtori CR, Mombelli G. Viability of developing CETP inhibitors. Cardiovasc Therapeut 2008; 26:135-146.
17. Miller NE. CETP inhibitors and cardiovascular disease: Time to think again. F1000Res 2014; 3:124.
18. Hovingh GK, Ray KK, Boekholdt SM. Is cholesteryl ester transfer protein inhibition an effective strategy to reduce cardiovascular risk? CETP as a target to lower CVD risk: suspension of disbelief? Circulation 2015; 132:433-440.
19. Schaefer EJ. Effects of cholesteryl ester transfer protein inhibitors on human lipoprotein metabolism: Why have they failed in lowering coronary heart disease risk? Curr Opin Lipidol 2013; 24:259-264.
20. Zhang Z, Yamashita S, Hirano K, et al. Expression of cholesteryl ester transfer protein in human atherosclerotic lesions and its implication in reverse cholesterol transport. Atherosclerosis 2001; 159:67-75.
21. Yamashita S, Maruyama T, Hirano K, et al. Molecular mechanisms, lipoprotein abnormalities and atherogenicity of hyperalphalipoproteinemia. Atherosclerosis 2000; 152:271-285.
22. Yamashita S, Sprecher DL, Sakai N, et al. Accumulation of apolipoprotein Erich high density lipoproteins in hyperalphalipoproteinemic human subjects with plasma cholesteryl ester transfer protein deficiency. J Clin Invest 1990; 86:688-695.
23. Asztalos BF, Horvath KV, Kajinami K, et al. Apolipoprotein composition of HDL in cholesteryl ester transfer protein deficiency. J Lipid Res 2004; 45:448-455.
24. Ohta T, Nakamura R, Takata K, et al. Structural and functional differences of subspecies of apoA-I-containing lipoprotein in patients with plasma cholesteryl ester transfer protein deficiency. J Lipid Res 1995; 36:696-704.
25. Matsuura F, Wang N, Chen W, et al. HDL fromCETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoEand ABCG1-dependent pathway. J Clin Invest 2006; 116:1435-1442.
26. Yamashita S, Ishigami M, Arai T, et al. Very high density lipoproteins induced by plasma CETP have a potent antiatherogenic function. Ann N Y Acad Sci 1995; 748:606-608.
27. Sakai N, Matsuzawa Y, Hirano K, et al. Detection of two species of low density lipoprotein particles in cholesteryl ester transfer protein deficiency. Arterioscler Thromb 1991; 11:71-79.
28. Ikewaki K, Nishiwaki M, Sakamoto T, et al. Increased catabolic rate of low density lipoproteins in humans with cholesteryl ester transfer protein deficiency. J Clin Invest 1995; 96:1573-1581.
29. Ikewaki K, Rader DJ, Sakamoto T, et al. Delayed catabolism of high density lipoprotein apolipoproteins A-I and A-II in human cholesteryl ester transfer protein deficiency. J Clin Invest 1993; 92:1650-1658.
30. Gomaraschi M, Ossoli A, Pozzi S, et al. eNOS activation by HDL is impaired in genetic CETP deficiency. PLoS One 2014; 9:e95925.
31. Yamashita S, Hui DY, Sprecher DL, et al. Total deficiency of plasma cholesteryl ester transfer protein in subjects homozygous and heterozygous for the intron 14 splicing defect. Biochem Biophys Res Commun 1990; 170:1346-1351.
32. Hirano K, Yamashita S, Funahashi T, et al. Frequency of intron 14 splicing defect of cholesteryl ester transfer protein gene in the Japanese general population - relation between the mutation and hyperalphalipoproteinemia. Atherosclerosis 1993; 100:85-90.
33. Maruyama T, Sakai N, Ishigami M, et al. Prevalence and phenotypic spectrum of cholesteryl ester transfer protein gene mutations in Japanese hyperalphalipoproteinemia. Atherosclerosis 2003; 166:177-185.
34. Takahashi K, Jiang XC, Sakai N, et al. A missense mutation in the cholesteryl ester transfer protein gene with possible dominant effects on plasma high density lipoproteins. J Clin Invest 1993; 92:2060-2064.
35. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010; 466:707-713.
36. Glueck CJ, Gartside P, Fallat RW, et al. Longevity syndromes: familial hypobeta and familial hyperalpha lipoproteinemia. J Lab Clin Med 1976; 88:941-957.
37. Zhong S, Sharp DS, Grove JS, et al. Increased coronary heart disease in Japanese-American men with mutation in the cholesterylester transfer protein gene despite increase HDL levels. J Clin Invest 1996; 97:2917-2923.
38. Curb JD, Abbott RD, Rodriguez BL, et al. A prospective study of HDL-C and cholesteryl ester transfer protein gene mutations and the risk of coronary heart disease in the elderly. J Lipid Res 2004; 45:948-953.
39. de Grooth GJ, Klerkx AH, Stroes ES, et al. A review of CETP and its relation to atherosclerosis. J Lipid Res 2004; 45:1967-1974.
40. Dullaart RP, Sluiter WJ. Common variation in the CETP gene and the implications for cardiovascular disease and its treatment: An updated analysis. Pharmacogenomics 2008; 9:747-763.
41. Thompson A, Di Angelantonio E, Sarwar N, et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. JAMA 2008; 299:2777-2788.
42. Corella D, Carrasco P, Amiano P, et al. Common cholesteryl ester transfer protein gene variation related to high-density lipoprotein cholesterol is not associated with decreased coronary heart disease risk after a 10-year followup in a Mediterranean cohort: Modulation by alcohol consumption. Atherosclerosis 2010; 211:531-538.
43. Marschang P, Sandhofer A, Ritsch A, et al. Plasma cholesteryl ester transfer protein concentrations predict cardiovascular events in patients with coronary artery disease treated with pravastatin. J Intern Med 2006; 260:151-159.
44. Vasan RS, Pencina MJ, Robins SJ, et al. Association of circulating cholesteryl ester transfer protein activity with incidence of cardiovascular disease in the community. Circulation 2009; 120:2414-2420.
45. Robins SJ, Lyass A, Brocia RW, et al. Plasma lipid transfer proteins and cardiovascular disease. The Framingham Heart Study. Atherosclerosis 2013; 228:230-236.
46. Ritsch A, Scharnagl H, Eller P, et al. Cholesteryl ester transfer protein and mortality in patients undergoing coronary angiography: The Ludwigshafen Risk and Cardiovascular Health study. Circulation 2010; 121:366-374.
47. Scharnagl H, Heuschneider C, Sailer S, et al. Decreased cholesterol efflux capacity in patients with low cholesteryl ester transfer protein plasma levels. Eur J Clin Invest 2014; 44:395-401.
48. Duwensee K, Breitling LP, Tancevski I, et al. Cholesteryl ester transfer protein in patients with coronary heart disease. Eur J Clin Invest 2010; 40:616-622.
49. Borggreve SE, Hillege HL, Wolffenbuttel BH, et al. An increased coronary risk is paradoxically associated with common cholesteryl ester transfer protein gene variations that relate to higher high-density lipoprotein cholesterol: A population-based study. J Clin Endocrinol Metab 2006; 91:3382- 3388.
50. Borggreve SE, de Vries R, Dallinga-Thie GM, et al. The ability of plasma to stimulate fibroblast cholesterol efflux is associated with the -629C!A cholesteryl ester transfer protein promoter polymorphism: Role of lecithin:cholesterol acyltransferase activity. Biochim Biophys Acta 2008; 1781:10-15.
51. Borggreve SE, Hillege HL, Dallinga-Thie GM, et al. High plasma cholesteryl ester transfer protein levels may favour reduced incidence of cardiovascular events in men with low triglycerides. Eur Heart J 2007; 28:1012-1018.
52. Khera AV, Wolfe ML, Cannon CP, et al. On-statin cholesteryl ester transfer protein mass and risk of recurrent coronary events (from the pravastatin or atorvastatin evaluation and infection therapy-Thrombolysis in myocardial infarction 22 [PROVE IT-TIMI 22] study). Am J Cardiol 2010; 106:451-456.
53. Hirano K-I, Yamashita S, Kuga Y, et al. Atherosclerosis disease in marked hyperalphalipoproteinemia. Combined reduction of cholesteryl ester transfer protein and hepatic triglyceride lipase. Arterioscl Thromb Vasc Biol 1995; 15:1849-1856.
54. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010; 363:2406- 2415.
55. && ACCELERATE. Presented at American College of Cardiology Scientific Sessions, April 2016. Slide available online at http://www.clinicaltrialresults.org/Slides/ACC%202016/Nicholls-ACCELERATEforreview.
56. Niesor EJ, Magg C, Ogawa N, et al. Modulating cholesteryl ester transfer protein activity maintains efficient preb-HDL formation and increases reverse cholesterol transport. J Lipid Res 2010; 51:3443-3454.
57. Nicholls SJ, Ruotolo G, Brewer HB, et al. Cholesterol efflux capacity and prebeta-1 HDL concentrations are increased in dyslipidemic patients treated with evacetrapib. J Am Coll Cardiol 2015; 66:2201-2210.
58. Yvan-Charvet L, Matsuura F, Wang N, et al. Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arterioscler Thromb Vasc Biol 2007; 27:1132-1138.
59. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007; 356:1304- 1316.
60. Kastelein JJ, van Leuven SI, Burgess L, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007; 356:1620-1630.
61. Bots ML, Visseren FL, Evans GW, et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): A randomised, double-blind trial. Lancet 2007; 370:153-160.
62. Vergeer M, Bots ML, van Leuven SI, et al. Cholesteryl ester transfer protein inhibitor torcetrapib and off-Target toxicity: A pooled analysis of the rating atherosclerotic disease change by imaging with a new CETP inhibitor (RADIANCE) trials. Circulation 2008; 118:2515-2522.
63. Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel noninvasive multimodality imaging (dal- PLAQUE): A randomised clinical trial. Lancet 2011; 378:1547-1559.
64. Lüscher TF, Taddei S, Kaski JC, et al. Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: The dal- VESSEL randomized clinical trial. Eur Heart J 2012; 33:857-865.
65. https://clinicaltrials.gov/ct2/show/NCT01059682?term=NCT01059682&rank=1 [Accessed 12 July 2016].
66. Ray KK, Ditmarsch M, Kallend D, et al. The effect of cholesteryl ester transfer protein inhibition on lipids, lipoproteins, and markers of HDL function after an acute coronary syndrome: The dal-ACUTE randomized trial. Eur Heart J 2014; 35:1792-1800.
67. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012; 367:2089-2099.
68. Tardif JC, Rhéaume E, Lemieux Perreault LP, et al. Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ Cardiovasc Genet 2015; 8:372-382.
69. Nicholls SJ, Brewer HB, Kastelein JJ, et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: A randomized controlled trial. JAMA 2011; 306:2099-2109.
70. Nicholls SJ, Lincoff AM, Barter PJ, et al. Assessment of the clinical effects of cholesteryl ester transfer protein inhibition with evacetrapib in patients at high-risk for vascular outcomes: Rationale and design of the ACCELERATE trial. Am Heart J 2015; 170:1061-1069.
71. Krishna R, Anderson MS, Bergman AJ, et al. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: Two double-blind, randomised placebo-controlled phase I studies. Lancet 2007; 370:1907-1914.
72. Gotto AM Jr, Cannon CP, Li XS, et al. Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease. Am J Cardiol 2014; 113:76-83.
73. Gotto AM Jr, Kher U, Chatterjee MS, et al. Lipids, safety parameters, and drug concentrations after an additional 2 years of treatment with anacetrapib in the DEFINE study. J Cardiovasc Pharmacol Ther 2014; 19:543-549.
74. Hartmann G, Kumar S, Johns D, et al. Disposition into adipose tissue determines accumulation and elimination kinetics of the cholesteryl ester transfer protein inhibitor anacetrapib in mice. Drug Metab Dispos 2016; 44:428-434.
75. Clinical trial.gov. REVEAL: Randomized evaluation of the effects of anacetrapib through Lipid-modification. 2010; http://clinicaltrials.gov/ct2/show/NCT01252953.
76. Ford J, Lawson M, Fowler D, et al. Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. Br J Clin Pharmacol 2014; 78:498- 508.
77. Hovingh GK, Kastelein JJ, van Deventer SJ, et al. Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): A randomised, double-blind, placebo-controlled phase 2 trial. Lancet 2015; 386:452-460.
78. Vakalopoulos A, Schmeck C, Thutewohl M, et al. Chromanol derivatives -A novel class of CETP inhibitors. Bioorg Med Chem Lett 2011; 21:488-491.
79. Boettcher MF, Heinig R, Schmeck C, et al. Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein. Br J Clin Pharmacol 2012; 73:210-218.
80. Miyosawa K, Watanabe Y, Murakami K, et al. New CETP inhibitor K-312 reduces PCSK9 expression: A potential effect on LDL cholesterol metabolism. Am J Physiol Endocrinol Metab 2015; 309:E177-E190.
81. Briel M, Ferreira-Gonzalez I, You JJ, et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ 2009; 338:b92.
82. Keene D, Price C, Shun-Shin MJ, et al. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-Analysis of randomised controlled trials including 117 411 patients. BMJ 2014; 349:g4379.
83. Hourcade-Potelleret F, Laporte S, Lehnert V, et al. Clinical benefit from pharmacological elevation of high-density lipoprotein cholesterol: meta-regression analysis. Heart 2015; 101:847-853.
84. Ueda Y, Gong E, Royer L, et al. Relationship between expression levels and atherogenesis in scavenger receptor class B, type I transgenics. J Biol Chem 2000; 275:20368-20373.
85. Braun A, Trigatti BL, Post MJ, et al. Loss of SR-BI expression leads to the early onset of occlusive atherosclerotic coronary artery disease, spontaneous myocardial infarctions, severe cardiac dysfunction, and premature death in apolipoprotein E-deficient mice. Circ Res 2002; 90:270-276.
86. Huszar D, Varban ML, Rinninger F, et al. Increased LDL cholesterol and atherosclerosis in LDL receptor-deficient mice with attenuated expression of scavenger receptor B1. Arterioscler Thromb Vasc Biol 2000; 20:1068- 1073.
87. Harder C, Lau P, Meng A, et al. Cholesteryl ester transfer protein (CETP) expression protects against diet induced atherosclerosis in SR-BI deficient mice. Arterioscler Thromb Vasc Biol 2007; 27:858-864.
88. Zanoni P, Khetarpal SA, Larach DB, et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science 2016; 351:1166-1171.
89. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: A Mendelian randomisation study. Lancet 2012; 380:572-580.
90. Hu X, Dietz JD, Xia C, et al. Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition. Endocrinology 2009; 150:2211-2219.
91. Forrest MJ, Bloomfield D, Briscoe RJ, et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompanied by increased circulating levels of aldosterone. Br J Pharmacol 2008; 154:1465-1473.
92. Levine DM, Parker TS, Donnelly TM, et al. In vivo protection against endotoxin by plasma high density lipoprotein. Proc Natl Acad Sci U S A 1993; 90:12040-12044.
93. Clark RW, Cunningham D, Cong Y, et al. Assessment of cholesteryl ester transfer protein inhibitors for interaction with proteins involved in the immune response to infection. J Lipid Res 2010; 51:967-974.
94. Liu S, Mistry A, Reynolds JM, et al. Crystal structures of cholesteryl ester transfer protein in complex with inhibitors. J Biol Chem 2012; 287:37321-37329.
95. Rios FJ, Neves KB, Nguyen Dinh Cat A, et al. Cholesteryl ester-Transfer protein inhibitors stimulate aldosterone biosynthesis in adipocytes through Nox-dependent processes. J Pharmacol Exp Ther 2015; 353:27-34.
96. Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989; 79:8-15.
97. Fulcher J, O'Connell R, Voysey M, et al., Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and safety of LDL-lowering therapy among men and women: meta-Analysis of individual data from 174 000 participants in 27 randomised trials. Lancet 2015; 385:1397-1405.
98. Di Angelantonio E, Sarwar N, Perry P, et al., Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009; 302:1993-2000.
99. van der Steeg WA, Holme I, Boekholdt SM, et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: The IDEAL and EPIC-Norfolk studies. J Am Coll Cardiol 2008; 51:634-642.
100. Huang Z, Inazu A, Kawashiri MA, et al. Dual effects on HDL metabolism by cholesteryl ester transfer protein inhibition in HepG2 cells. Am J Physiol Endocrinol Metab 2003; 284:E1210-E1219.
101. Brousseau ME, Diffenderfer MR, Millar JS, et al. Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion. Arterioscler Thromb Vasc Biol 2005; 25:1057-1064.
102. Reyes-Soffer G, Millar JS, Ngai C, et al. Cholesteryl ester transfer protein inhibition with anacetrapib decreases fractional clearance rates of highdensity lipoprotein apolipoprotein A-I and plasma cholesteryl ester transfer protein. Arterioscler Thromb Vasc Biol 2016; 36:994-1002.
103. Gauthier A, Lau P, Zha X, et al. Cholesteryl ester transfer protein directly mediates selective uptake of high density lipoprotein cholesteryl esters by the liver. Arterioscler Thromb Vasc Biol 2005; 25:2177-2184.
104. Otvos JD, Collins D, Freedman DS, et al. Low-density lipoprotein and highdensity lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation 2006; 113:1556-1563.
105. Kontush A, Chapman MJ. Functionally defective high-density lipoprotein: A new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacol Rev 2006; 58:342-374.
106. Vaisar T, Pennathur S, Green PS, et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest 2007; 117:746-756.
107. Kontush A, Chapman MJ. Antiatherogenic small, dense HDL - guardian angel of the arterial wall? Nat Clin Pract Cardiovasc Med 2006; 3:144-153.
108. Genest J. The Yin and Yang of high-density lipoprotein cholesterol. J Am Coll Cardiol 2008; 51:643-644.
109. Yvan-Charvet L, Kling J, Pagler T, et al. Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib. Arterioscler Thromb Vasc Biol 2010; 30:1430-1438.
110. Krauss RM, Wojnooski K, Orr J, et al. Changes in lipoprotein subfraction concentration and composition in healthy individuals treated with the CETP inhibitor anacetrapib. J Lipid Res 2012; 53:540-547.
111. Millar JS, Brousseau ME, Diffenderfer MR, et al. Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on apolipoprotein B100 metabolism in humans. Arterioscler Thromb Vasc Biol 2006; 26:1350-1356.
112. Millar JS, Brousseau ME, Diffenderfer MR, et al. Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on VLDL apolipoprotein E metabolism. J Lipid Res 2008; 49:543-549.
113. Millar JS, Reyes-Soffer G, Jumes P, et al. Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects. J Clin Invest 2015; 125:2510-2522.
114. Krauss RM, Pinto CA, Liu Y, et al. Changes in LDL particle concentrations after treatment with the cholesteryl ester transfer protein inhibitor anacetrapib alone or in combination with atorvastatin. J Clin Lipidol 2015; 9:93-102.
115. Villard EF, El Khoury P, Duchene E, et al. Elevated CETP activity improves plasma cholesterol efflux capacity from human macrophages in women. Arterioscler Thromb Vasc Biol 2012; 32:2341-2349.
116. Tanigawa H, Billheimer JT, Tohyama J, et al. Expression of cholesteryl ester transfer protein in mice promotes macrophage reverse cholesterol transport. Circulation 2007; 116:1267-1273.
117. Tchoua U, D'Souza W, Mukhamedova N, et al. The effect of cholesteryl ester transfer protein overexpression and inhibition on reverse cholesterol transport. Cardiovasc Res 2008; 77:732-739.
118. Gautier T, Masson D, Lagrost L. The potential of cholesteryl ester transfer protein as a therapeutic target. Expert Opin Ther Targets 2016; 20:47-59.
119. Chiesa G, Michelagnoli S, Cassinotti M, et al. Mechanisms of high-density lipoprotein reduction after probucol treatment: changes in plasma cholesterol esterification/transfer and lipase activities. Metabolism 1993; 42:229-235.
120. Franceschini G, Sirtori M, Vaccarino V, et al. Mechanisms of HDL reduction after probucol. Changes in HDL subfractions and increased reverse cholesteryl ester transfer. Arteriosclerosis 1989; 9:462-469.
121. Hirano K, Ikegami C, Tsujii K, et al. Probucol enhances the expression of human hepatic scavenger receptor class B type I, possibly through a species-specific mechanism. Arterioscler Thromb Vasc Biol 2005; 25:2422-2427.
122. Ishigami M, Yamashita S, Sakai N, et al. High-density lipoproteins from probucol-Treated patients have increased capacity to promote cholesterol efflux from mouse peritoneal macrophages loaded with acetylated lowdensity lipoproteins. Eur J Clin Invest 1997; 27:285-292.
123. Inagaki M, Nakagawa-Toyama Y, Nishida M, et al. Effect of probucol on antioxidant properties of HDL in patients with heterozygous familial hypercholesterolemia. J Atheroscler Thromb 2012; 19:643-656.
124. Matsuzawa Y, Yamashita S, Funahashi T, et al. Selective reduction of cholesterol in HDL2 fraction by probucol in familial hypercholesterolemia and hyperHDL2 cholesterolemia with abnormal cholesteryl ester transfer. Am J Cardiol 1988; 62:66B-72B.
125. Miettinen TA, Huttunen JK, Naukkarinen V, et al. Multifactorial primary prevention of cardiovascular diseases in middle-Age men. Risk factor changes, incidence, and mortality. JAMA 1985; 254:2097- 2102.
126. Sawayama Y, Shimizu C, Maeda N, et al. Effects of probucol and pravastatin on common carotid atherosclerosis in patients with asymptomatic hypercholesterolemia. Fukuoka Atherosclerosis Trial (FAST). J Am Coll Cardiol 2002; 39:610-616.
127. Yamashita S, Bujo H, Arai H, et al. Long-Term probucol treatment prevents secondary cardiovascular events: A cohort study of patients with heterozygous familial hypercholesterolemia in Japan. J Atheroscler Thromb 2008; 15:292-303.
128. Kasai T, Miyauchi K, Kubota N, et al. Probucol therapy improves long-Term (>10-year) survival after complete revascularization: A propensity analysis. Atherosclerosis 2012; 220:463-469.
129. Yamashita S, Masuda D, Matsuzawa Y. Did we abandon probucol too soon? Curr Opin Lipidol 2015; 26:304-316.
130. Toth PP, Barter PJ, Rosenson RS, et al. High-density lipoproteins: A consensus statement from the National Lipid Association. J Clin Lipidol 2013; 7:484-525.