And then there were acyl coenzyme A:cholesterol acyl transferase inhibitors

Current Opinion in Lipidology

Volumn 17, Issue 4, 2006, Pages 426-430

  Meuwese, Marijn C ^a   Franssen, Remco ^a   Stroes, Erik S G ^a   Kastelein, John J P ^a  

^a ACADEMIC MEDICAL CENTER   (Netherlands)

Author keywords

ACAT inhibition; Atherosclerosis; Cholesterol; Foam cell

Indexed keywords

1 [2,4 DIFLUORO 6 [2 [4 (2,2 DIMETHYLPROPYL)PHENYL]ETHYL]PHENYL] 3 HEPTYLUREA; ATORVASTATIN; AVASIMIBE; CHOLESTEROL; CHOLESTEROL ACYLTRANSFERASE INHIBITOR; CHOLESTEROL ESTER; CL 2777082; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LECIMIBIDE; PACTIMIBE; PRAVASTATIN; UNCLASSIFIED DRUG;

ATHEROMA; ATHEROSCLEROSIS; CARDIOVASCULAR DISEASE; CHOLESTEROL ESTERIFICATION; CHOLESTEROL TRANSPORT; CLINICAL TRIAL; CORONARY ARTERY DISEASE; DYSLIPIDEMIA; FAMILIAL HYPERCHOLESTEROLEMIA; HUMAN; HYPERLIPIDEMIA; INTESTINE; ISCHEMIC HEART DISEASE; LIVER; MACROPHAGE; NONHUMAN; PRIORITY JOURNAL; REVIEW; TANGIER DISEASE;

ANIMALS; CARDIOVASCULAR DISEASES; ENZYME INHIBITORS; HUMANS; STEROL O-ACYLTRANSFERASE;

ANIMALIA; RODENTIA;

EID: 33746082034     PISSN: 09579672     EISSN: None     Source Type: Journal    
DOI: 10.1097/01.mol.0000236369.50378.6e     Document Type: Review

References (47)

1. Baigent C, Keech A, Kearney PM, et al. Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005; 366:1267-1278.
2. Meiner VL, Cases S, Myers HM, et al. Disruption of the acyl-CoA:cholesterol acyltransferase gene in mice: evidence suggesting multiple cholesterol esterification enzymes in mammals. Proc Natl Acad Sci U S A 1996; 93: 14041-14046.
3. Wang H, Germain SJ, Benfield PP, Gillies PJ. Gene expression of acyl-coenzyme-A:cholesterol acyltransferase is upregulated in human monocytes during differentiation and foam cell formation. Arterioscler Thromb Vasc Biol 1996; 16:809-814.
4. Miyazaki A, Sakashita N, Lee O, et al. Expression of ACAT-1 protein in human atherosclerotic lesions and cultured human monocytes-macrophages. Arterioscler Thromb Vasc Biol 1998; 18:1568-1574.
5. Anderson RA, Joyce C, Davis M, et al. Identification of a form of acyl-CoA:cholesterol acyltransferase specific to liver and intestine in nonhuman primates. J Biol Chem 1998; 273:26747-26754.
6. Accad M, Smith SJ, Newland DL, et al. Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl-CoA:cholesterol acyltransferase 1. J Clin Invest 2000; 105:711-719.
7. Fazio S, Major AS, Swift LL, et al. Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages. J Clin Invest 2001; 107:163-171.
8. Yagyu H, Kitamine T, Osuga J, et al. Absence of ACAT-1 attenuates atherosclerosis but causes dry eye and cutaneous xanthomatosis in mice with congenital hyperlipidemia. J Biol Chem 2000; 275:21324-21330.
9. Repa JJ, Buhman KK, Farese RV Jr, et al. ACAT2 deficiency limits cholesterol absorption in the cholesterol-fed mouse: impact on hepatic cholesterol homeostasis. Hepatology 2004; 40:1088-1097.
10. Buhman KK, Accad M, Novak S, et al. Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med 2000; 6:1341-1347.
11. Willner EL, Tow B, Buhman KK, et al. Deficiency of acyl-CoA:cholesterol acyltransferase 2 prevents atherosclerosis in apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A 2003; 100:1262-1267.
12. Robertson DG, Breider MA, Milad MA. Preclinical safety evaluation of avasimibe in beagle dogs: an ACAT inhibitor with minimal adrenal effects. Toxicol Sci 2001; 59:324-334.
13. Bocan TM, Krause BR, Rosebury WS, et al. The ACAT inhibitor avasimibe reduces macrophages and matrix metalloproteinase expression in atherosclerotic lesions of hypercholesterolemic rabbits. Arterioscler Thromb Vasc Biol 2000; 20:70-79.
14. Post SM, Zoeteweij JP, Bos MH, et al. Acyl-coenzyme A:cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7alpha-hydroxylase in cultured rat hepatocytes and in vivo in the rat. Hepatology 1999; 30:491-500.
15. Delsing DJ, Offerman EH, van Duyvenvoorde W, et al. Acyl-CoA:cholesterol acyltransferase inhibitor avasimibe reduces atherosclerosis in addition to its cholesterol-lowering effect in ApoE*3-Leiden mice. Circulation 2001; 103:1778-1786.
16. Nicolosi RJ, Wilson TA, Krause BR. The ACAT inhibitor, CI-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters. Atherosclerosis 1998; 137:77-85.
17. Ramharack R, Spahr MA, Sekerke CS, et al. CI-1011 lowers lipoprotein(a) and plasma cholesterol concentrations in chow-fed cynomolgus monkeys. Atherosclerosis 1998; 136:79-87.
18. Harris WS, Dujovne CA, von Bergmann K, et al. Effects of the ACAT inhibitor CL 277 082 on cholesterol metabolism in humans. Clin Pharmacol Ther 1990; 48:189-194.
19. Hainer JW, Terry JG, Connell JM, et al. Effect of the acyl-CoA:cholesterol acyltransferase inhibitor DuP 128 on cholesterol absorption and serum cholesterol in humans. Clin Pharmacol Ther 1994; 56:65-74.
20. Peck RW, Wiggs R, Posner J. The tolerability, pharmacokinetics and lack of effect on plasma cholesterol of 447C88, an acyl-CoA:cholesterol acyltransferase inhibitor with low bioavailability, in healthy volunteers. Eur J Clin Pharmacol 1995; 49:243-249.
21. Insull W Jr, Koren M, Davignon J, et al. Efficacy and short-term safety of a new ACAT inhibitor, avasimibe, on lipids, lipoproteins, and apolipoproteins, in patients with combined hyperlipidemia. Atherosclerosis 2001; 157:137-144.
22. Raal FJ, Marais AD, Klepack E, et al. an ACAT inhibitor, enhances the lipid lowering effect of atorvastatin in subjects with homozygous familial hypercholesterolemia. Atherosclerosis 2003; 171:273-279.
23. Tardif JC, Gregoire J, L'Allier PL, et al. Avasimibe and Progression of Lesions on UltraSound (A-PLUS) Investigators. Effects of the acyl coenzyme A:cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions. Circulation 2004; 110:3372-3377.
24. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) Investigators. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005; 352:29-38.
25. Nissen SE, Tuzcu EM, Brewer HB, et al., and the ACAT Intravascular Treatment Evaluation (ACTIVATE) Investigators. Effect of ACAT inhibition on the progression of coronary atherosclerosis. New Engl J Med 2006; 354 (12):1253-1263.
26. Daiichi Sankyo Company, Limited. Discontinuation of clinical studies of CS-505. October 26, 2005. Press release available online at www.sankyo.co.jp/ english/release/2005/20051026cs505eng.html.
27. Kharbanda RK, Wallace S, Walton B, et al. Systemic acyl-CoA:cholesterol acyltransferase inhibition reduces inflammation and improves vascular function in hypercholesterolemia. Circulation 2005; 111:804-807. This is the first study that showed a positive effect of an ACAT inhibitor on inflammation and endothelial function in humans. The number of participants, however, is small (n = 21) and of all inflammatory parameters, only an effect on circulating levels of TNF-alpha was observed.
28. Bocan TM, Krause BR, Rosebury WS, et al. The combined effect of inhibiting both ACAT and HMG-CoA reductase may directly induce atherosclerotic lesion regression. Atherosclerosis 2001; 157:97-105.
29. Akopian D, Medh JD. Genetics and molecular biology: macrophage ACAT depletion - mechanisms of atherogenesis. Curr Opin Lipidol 2006; 17: 85-88. Excellent short summary of the possible explanations of the pro-atherogenic effects of ACAT inhibition in humans.
30. Warner GJ, Stoudt G, Bamberger M, et al. Cell toxicity induced by inhibition of acyl coenzyme A:cholesterol acyltransferase and accumulation of unesterified cholesterol. J Biol Chem 1995; 270:5772-5778.
31. Rodriguez A, Ashen MD, Chen ES. ACAT1 deletion in murine macrophages associated with cytotoxicity and decreased expression of collagen type 3A1. Biochem Biophys Res Commun 2005; 331:61-68.
32. Qin C, Nagao T, Grosheva I, et al. Elevated plasma membrane cholesterol content alters macrophage signalling and function. Arterioscler Thromb Vasc Biol 2006; 26:372-378. This study shows that macrophage behavior is altered when membrane cholesterol levels are elevated in vitro. Macrophages were treated with acetylated LDL and an ACAT inhibitor. The subsequent accumulation of free cholesterol affected cell spreading, adhesion, migration and signaling. These changes might contribute to the accumulation of macrophages in atherosclerotic plaque in vivo.
33. Su YR, Dove DE, Major AS, et al. Reduced ABCA1-mediated cholesterol efflux and accelerated atherosclerosis in apolipoprotein E-deficient mice lacking macrophage-derived ACAT1. Circulation 2005; 111: 2373-2381. This study showed the influence of both ACAT and apoE on atherogenesis. Most importantly, the authors show that cholesterol efflux was significantly reduced in ACAT1-deficient macrophages compared with normal macrophages, regardless of apoE expression. This was accompanied by an increase in ABCA1 mRNA, but a decrease in ABCA1 protein, indicating protein instability.
34. Dove DE, Su YR, Swift LL, et al. ACAT1 deficiency increases cholesterol synthesis in mouse peritoneal macrophages. Atherosclerosis, [Epub ahead of print].
35. Cignarella A, Engel T, von Eckardstein A, et al. Pharmacological regulation of cholesterol efflux in human monocyte-derived macrophages in the absence of exogenous cholesterol acceptors. Atherosclerosis 2005; 179:229-236. This study shows that spontaneous cholesterol efflux from human macrophages in vitro is not necessarily promoted by increasing intracellular free cholesterol.
36. Dove DE, Su YR, Zhang W, et al. ACAT1 deficiency disrupts cholesterol efflux and alters cellular morphology in macrophages. Atheroscler Thromb Vasc Biol 2005; 25:128-134. The effect of ACAT1 deficiency in macrophages on cholesterol efflux, cholesterol storage and cellular morphology was assessed in this study to explore the mechanism behind the increase in atherosclerosis in ACAT1 knockout mice. As expected, ACAT1-deficient cells had a lower content of esterified cholesterol and increased accumulation of free cholesterol compared with control macrophages. Surprisingly, a decreased efflux of cellular cholesterol was observed, despite increased ABCA1 mRNA levels. In contrast, efflux of lipoprotein-derived cholesterol was increased.
37. Sahi J, Milad MA, Zheng X, et al. Avasimibe induces CYP3A4 and multiple drug resistance protein 1 gene expression through activation of the pregnane X receptor. J Pharmacol Exp Ther 2003; 306:1027-1034.
38. Smith JL, Rangaraj K, Simpson R, et al. Quantitative analysis of the expression of ACAT genes in human tissues by real-time PCR. J Lipid Res 2004; 45:686-696.
39. Hakamata H, Miyazaki A, Sakai M, et al. Species difference in cholesteryl ester cycle and HDL-induced cholesterol efflux from macrophage foam cells. Arterioscler Thromb 1994; 14:1860-1865.
40. Chang TY, Chang CC, Lin S, et al. Roles of acyl coenzyme A:cholesterol acyltransferase-1 and -2. Curr Opin Lipidol 2001; 12:289-296.
41. Rong JX, Kusunoki J, Oelkers P, et al. ACAT inhibition in rat and human aortic smooth muscle cells is nontoxic and retards foam cell formation. Arterioscler Thromb Vasc Biol 2005; 25:122-127. This study showed that accumulation of free cholesterol due to ACAT inhibition is less toxic to smooth muscle cells than to macrophages in vivo. More importantly, foam cell formation from aortic smooth muscle cells was suppressed.
42. Fazio S, Dove DE, Linton MF. ACAT inhibition: bad for macrophages, good for smooth muscle cells? Arterioscler Thromb Vasc Biol 2005; 25:7-9. The authors reviewed the study by Rong et al. and envisage application of ACAT inhibitors in lesions rich in smooth muscle cells.
43. Hutter-Paier B, Huttunen HJ, Puglielli L, et al. The ACAT inhibitor CP-113 818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease. Neuron 2004; 44:227-238.
44. Leon C, Hill JS, Wasan KM. Potential role of acyl coenzyme A:cholesterol transferase (ACAT) inhibitors as hypolipidemic and antiatherosclerosis drugs. Pharm Res 2005; 22:1578-1588. The focus of this review is the potential clinical use of ACAT inhibitors, also discussing the ACAT genes, the protein structure, its cholesterol-binding domains and its regulation. ACAT is still seen as a promising target to treat atherosclerosis and hypercholesterolemia, especially by development of bioinformatics strategies and tissue-specific drug delivery.
45. Rudel LL, Lee RG, Parini P. ACAT2 is a target for treatment of coronary heart disease associated with hypercholesterolemia. Arterioscler Thromb Vasc Biol 2005; 25:1112-1118. The authors reviewed the different functions of ACAT1 and ACAT2 and advocate a strategy of selective ACAT2 inhibition for treatment of coronary heart disease. Of special interest is the hypothesis that ACAT2 inhibition in intestinal cells leads to ABCA1-mediated efflux of cholesterol onto high-density lipoprotein. Furthermore, they suggest that there are sufficient mechanisms for disposing of free cholesterol in intestinal cells and liver, to avoid toxicity as found in macrophages.
46. Miyazaki A, Kanome T, Watanabe T. Inhibitors of acyl-coenzyme A:cholesterol acyltransferase. Curr Drug Targets Cardiovasc Haematol Disord 2005; 5:463-469.
47. Kellner-Weibel G, Jerome WG, Small DM, et al. Effects of intracellular free cholesterol accumulation on macrophage viability: a model for foam cell death. Atheroscler Thromb Vasc Biol 1998; 18:423-431.