The Nine Lives of ACAT Inhibitors
2006; Lippincott Williams & Wilkins; Volume: 26; Issue: 8 Linguagem: Inglês
10.1161/01.atv.0000227511.35456.90
ISSN1524-4636
Autores Tópico(s)Lipoproteins and Cardiovascular Health
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 26, No. 8The Nine Lives of ACAT Inhibitors Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBThe Nine Lives of ACAT Inhibitors Robert V. FareseJr Robert V. FareseJrRobert V. FareseJr From the Gladstone Institute of Cardiovascular Disease; and the Cardiovascular Research Institute, the Departments of Medicine and Biochemistry & Biophysics, and the Diabetes Center, University of California, San Francisco. Originally published1 Aug 2006https://doi.org/10.1161/01.ATV.0000227511.35456.90Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1684–1686Atherosclerosis is the product of excessive lipid accumulation and inflammation in the artery wall. The lipid that tops every list of suspects is cholesterol, which is the primary lipid in low-density lipoproteins (LDL). Cholesterol exists either as a simple molecule or as cholesterol esters, in which the hydroxyl group is linked to a fatty acyl moiety. In cells, cholesterol esters are synthesized in an intracellular reaction catalyzed by acyl coenzyme A (CoA):cholesterol acyltransferase (ACAT) enzymes.1,2 Owing to the discoveries of cholesterol esters in arterial lesions in 19103 and of ACAT activity in the mid 1900s,4 inhibiting ACAT has been considered as a strategy for preventing or treating atherosclerosis. Over the past 25 years, interest in ACAT inhibitors has waxed and waned as new studies advance knowledge in the field. Prominently reported and disappointing results from a recent human trial of an ACAT inhibitor5 dampened enthusiasm for this potential therapy. However, a study by Bell et al in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology6 revives the idea of targeting ACAT enzymes and highlights a key unanswered question: Can ACAT2-specific inhibitors lower plasma cholesterol and treat or prevent atherosclerosis?See page 1814After the discovery of the ACAT reaction, two rationales for inhibiting ACAT emerged. One, in retrospect, was perhaps overly simplistic: blocking cholesterol esterification in macrophages would diminish macrophage "foam cell" formation and thereby decrease atherosclerotic lesion development. The other was to decrease hepatic and intestinal cholesterol ester formation, resulting in decreases in plasma levels of the atherogenic apolipoprotein B–containing lipoproteins, such as cholesterol ester–rich LDL and remnant lipoproteins derived from very low-density lipoproteins and chylomicrons. With these ideas in mind, pharmaceutical companies initiated drug discovery programs, and several potent inhibitors were discovered.1 Between 1980 and 1995, interest in ACAT inhibitors grew steadily, as reflected by a gradual increase in articles published on the subject (peaking at ≈30 per year in 1995). However, studies in humans showed that several compounds lacked efficacy for lowering cholesterol,7,8 some compounds exhibited toxicity in animal studies,9,10 and statins emerged to take their predominant role in the treatment of hypercholesterolemia. As a result, the idea of ACAT inhibitors as useful drugs lost vitality.In 1993, the ACAT field was resuscitated with the cloning of an ACAT gene,11 a heroic effort that took nearly a decade. ACAT investigation entered the molecular era, which afforded new approaches to elucidate the functions of the enzyme. Mice lacking the newly cloned gene were generated. These animals lacked cholesterol esters in macrophages and the adrenal cortex but had residual ACAT activity in the liver and small intestine,12 indicating that another ACAT gene existed. Three laboratories subsequently cloned a gene encoding ACAT2,13–15 which is expressed in the liver and small intestine. No other ACAT genes have been identified, suggesting that ACAT1 and ACAT2 are the only two ACAT enzymes in mammals.The discovery of two ACAT enzymes raised the question of whether selective ACAT inhibition would lower plasma cholesterol levels or treat atherosclerosis. Subsequent studies in mice afforded some predictions. Mice lacking ACAT1 exhibited toxic accumulation of unesterified cholesterol in the skin and brain in the setting of hypercholesterolemia,16,17 and mice with macrophages engineered to lack ACAT1 had increased atherosclerotic lesions in a mouse model of atherosclerosis.18 These results suggested that the inability to esterify cholesterol in macrophages could result in cellular toxicity, giving rise to cell death and inflammation, a concept supported by studies using ACAT inhibitors in cultured macrophages.19,20 Thus, it was predicted that ACAT1 inhibition would not be a good strategy and, in fact, could have detrimental consequences.1In contrast, mice lacking ACAT2 exhibited attractive metabolic findings. These included a restricted capacity to absorb cholesterol and protection against diet-induced hypercholesterolemia and gallstone formation.21,22 Further, they lacked cholesterol esters in their apolipoprotein B–containing lipoproteins and were protected from atherosclerosis in murine models of the disease.23 Mice lacking both ACAT2 and lecithin:cholesterol acyltransferase (LCAT), an enzyme that catalyzes cholesterol ester synthesis in the plasma lipoproteins, had virtually no cholesterol esters in the plasma and were highly resistant to atherosclerosis,24 underscoring the importance of plasma cholesterol esters in atherosclerosis. These studies in rodents raised the important question of whether ACAT2-specific inhibition would protect against atherosclerosis.In the past few years, enthusiasm for ACAT inhibitors again has again waxed and waned. Several studies in animals, primarily using nonselective inhibitors, showed promising results.25–27 However, two recent trials in humans were disappointing. In one, the nonselective inhibitor avasimibe, administered for 2 years to patients with atherosclerosis, did not reduce plaque volume.28 More recently, an 18-month study of patients with atherosclerosis treated with pactimibe also failed to show a reduction of plaque volume, and secondary plaque-related end points suggested a detrimental effect of the drug.5 However, there are caveats to interpreting the pactimibe study. First, the drug is reportedly nonselective.5 Second, no evidence suggested that therapeutic efficacy was achieved with respect to ACAT2 inhibition; plasma cholesterol levels were unaffected, suggesting that inhibition of liver and intestinal ACAT activity was insufficient. Nevertheless, the latter trial prompted the authors to pronounce the imminent death of ACAT inhibitors as a viable atherosclerosis therapy.The study of Bell et al in this issue6 breathes life back into the idea of ACAT2-specific inhibition. In atherosclerosis-prone mice, ACAT2 was specifically inhibited in the liver with antisense oligonucleotides. Biweekly intraperitoneal injections, which reduced ACAT2 expression by a remarkable 80%, decreased diet-induced hypercholesterolemia and sharply reduced cholesterol ester deposition in the aorta. It also reduced the levels of saturated and monounsaturated fatty acids in cholesterol esters in plasma LDL and increased the levels of polyunsaturated fatty acids. The latter findings reflect the increased relative contribution from LCAT. The antisense treatment did not affect ACAT2 expression in the small intestine, nor did it affect intestinal cholesterol absorption.The antisense approach is intriguing, particularly given the success of intermittent injections of antisense oligonucleotides to lower plasma apoB and cholesterol levels.29 The prolonged and marked knockdown of hepatic gene expression from a single dose of antisense oligonucleotides is impressive. However, one of the ACAT2 antisense oligonucleotides in the study of Bell et al was associated with liver toxicity, indicating the need for caution as antisense approaches move into human trials.A fundamental question remains: would ACAT2-specific inhibition in humans, either pharmacologically or with antisense oligonucleotides, prevent or reduce atherosclerosis? A key factor may be whether ACAT2 activity is as important in human liver as it is in mouse liver. ACAT activity in human liver is lower than in other species,30 and it is controversial whether ACAT is the predominant form in human hepatocytes.30,31 Another consideration is the relative contribution of ACAT enzymes to plasma cholesterol esters in humans. As noted above, cholesterol esters are also formed in plasma lipoproteins through a reaction catalyzed by LCAT, which contributes substantially to circulating cholesterol esters. Finally, ACAT2 expression has been reported to be upregulated in macrophages of atherosclerotic lesions,32 which current evidence suggests is not a good place for ACAT inhibition.Nevertheless, the findings of Bell et al suggest that ACAT2-specific inhibition needs to be tested. As the great physicist Richard Feynman liked to remind us, "The sole test of the validity of an idea is experiment." Until a potent and specific inhibitor of ACAT2 is tested in humans, the hypothesis remains untested. Meanwhile, the idea of using ACAT inhibitors to treat atherosclerosis is again moribund, awaiting an experiment to determine its fate.DisclosuresNone.FootnotesCorrespondence to Robert V. Farese Jr, University of California, San Francisco, 1650 Owens Street, San Francisco, CA 94158. E-mail [email protected] References 1 Buhman KF, Accad M, Farese RV Jr. Mammalian acyl-CoA:cholesterol acyltransferases. Biochim Biophys Acta. 2000; 1529: 142–154.CrossrefMedlineGoogle Scholar2 Chang TY, Chang CCY, Cheng D. Acyl-coenzyme A:cholesterol acyltransferase. Annu Rev Biochem. 1997; 66: 613–638.CrossrefMedlineGoogle Scholar3 Windaus A. Über den Gehalt normaler und atheromatöser Aorten an Cholesterin und Cholesterinestern. Hoppe-Seyler's Z Physiol Chem. 1910; 67: 174–176.CrossrefGoogle Scholar4 Goodman DS, Deykin D, Shiratori T. The formation of cholesterol esters with rat liver enzymes. J Biol Chem. 1964; 239: 1335–1345.CrossrefMedlineGoogle Scholar5 Nissen SE, Tuzcu EM, Brewer HB, Sipahi I, Nicholls SJ, Ganz P, Schoenhagen P, Waters DD, Pepine CJ, Crowe TD, Davidson MH, Deanfield JE, Wisniewski LM, Hanyok JJ, Kassalow LM. Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med. 2006; 354: 1253–1263.CrossrefMedlineGoogle Scholar6 Bell TA III, Brown JM, Graham MJ, Lemonidis KM, Crooke RM, Rudel LL. Liver-specific inhibition of acyl-CoA:cholesterol acyltransferase 2 with antisense oligonucleotides limits atherosclerosis development in apoB100-only LDLr−/− mice. Arterioscler Thromb Vasc Biol. 2006; 26: 1814–1820.LinkGoogle Scholar7 Harris WS, Dujovne CA, von Bergmann K, Neal J, Akester J, Windsor SL, Greene D, Look Z. Effects of the ACAT inhibitor CL 277,082 on cholesterol metabolism in humans. Clin Pharmacol Ther. 1990; 48: 189–194.CrossrefMedlineGoogle Scholar8 Hainer JW, Terry JG, Connell JM, Zyruk H, Jenkins RM, Shand DL, Gillies PJ, Livak KJ, Hunt TL, Crouse JR III. 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.CrossrefMedlineGoogle Scholar9 Dominick MA, Bobrowski WA, MacDonald JR, Gough AW. Morphogenesis of a zone-specific adrenocortical cytotoxicity in guinea pigs administered PD 132301-2, an inhibitor of acyl-CoA:cholesterol acyltransferase. Toxicol Pathol. 1993; 21: 54–62.CrossrefMedlineGoogle Scholar10 Dominick MA, McGuire EJ, Reindel JF, Bobrowski WF, Bocan TMA, Gough AW. Subacute toxicity of a novel inhibitor of acyl-CoA:cholesterol acyltransferase in beagle dogs. Fundam Appl Toxicol. 1993; 20: 217–224.CrossrefMedlineGoogle Scholar11 Chang CCY, Huh HY, Cadigan KM, Chang TY. Molecular cloning and functional expression of human acyl-coenzyme A:cholesterol acyltransferase cDNA in mutant Chinese hamster ovary cells. J Biol Chem. 1993; 268: 20747–20755.CrossrefMedlineGoogle Scholar12 Meiner VL, Cases S, Myers HM, Sande ER, Bellosta S, Schambelan M, Pitas RE, McGuire J, Herz J, Farese RV Jr. 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.CrossrefMedlineGoogle Scholar13 Cases S, Novak S, Zheng Y-W, Myers HM, Lear SR, Sande E, Welch CB, Lusis AJ, Spencer TA, Krause BR, Erickson SK, Farese RV Jr. ACAT-2, a second mammalian acyl-CoA:cholesterol acyltransferase. Its cloning, expression, and characterization. J Biol Chem. 1998; 273: 26755–26764.CrossrefMedlineGoogle Scholar14 Anderson RA, Joyce C, Davis M, Reagan JW, Clark M, Shelness GS, Rudel LL. Identification of a form of Acyl-CoA:cholesterol acyltransferase specific to liver and intestine in nonhuman primates. J Biol Chem. 1998; 273: 26747–26754.CrossrefMedlineGoogle Scholar15 Oelkers P, Behari A, Cromley D, Billheimer JT, Sturley SL. Characterization of two human genes encoding acyl coenzyme A:cholesterol acyltransferase-related enzymes. J Biol Chem. 1998; 273: 26765–26771.CrossrefMedlineGoogle Scholar16 Accad M, Smith SJ, Newland DL, Sanan DA, King LE Jr, Linton MF, Fazio S, Farese RV Jr. Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1. J Clin Invest. 2000; 105: 711–719.CrossrefMedlineGoogle Scholar17 Yagyu H, Kitamine T, Osuga J-I, Tozawa R-I, Chen Z, Kaji Y, Oka T, Perrey S, Tamura Y, Ohashi K, Okazaki H, Yahagi N, Shionoiri F, Iizuka Y, Harada K, Shimano H, Yamashita H, Gotoda T, Yamada N, Ishibashi S. 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.CrossrefMedlineGoogle Scholar18 Fazio S, Major AS, Swift LL, Gleaves LA, Accad M, Linton MF, Farese RV Jr. Increased atherosclerosis in LDL receptor–null mice lacking ACAT1 in macrophages. J Clin Invest. 2001; 107: 163–171.CrossrefMedlineGoogle Scholar19 Warner GJ, Stoudt G, Bamberger M, Johnson WJ, Rothblat GH. Cell toxicity induced by inhibition of acyl coenzyme A:cholesterol acyltransferase and accumulation of unesterified cholesterol. J Biol Chem. 1995; 270: 5772–5778.CrossrefMedlineGoogle Scholar20 Maxfield FR, Tabas I. Role of cholesterol and lipid organization in disease. Nature. 2005; 438: 612–621.CrossrefMedlineGoogle Scholar21 Buhman KK, Accad M, Novak S, Choi RS, Wong JS, Hamilton RL, Turley S, Farese RV Jr. Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med. 2000; 6: 1341–1347.CrossrefMedlineGoogle Scholar22 Repa JJ, Buhman KK, Farese RV Jr, Dietschy JM, Turley SD. ACAT2 deficiency limits cholesterol absorption in cholesterol-fed mice: Impact on hepatic cholesterol homeostasis. Hepatology. 2004; 40: 1088–1097.CrossrefMedlineGoogle Scholar23 Willner EL, Tow B, Buhman KK, Wilson M, Sanan DA, Rudel LL, Farese RV Jr. 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.CrossrefMedlineGoogle Scholar24 Lee RG, Kelly KL, Sawyer JK, Farese RV Jr, Parks JS, Rudel LL. Plasma cholesteryl esters provided by lecithin:cholesterol acyltransferase and acyl-coenzyme A:cholesterol acyltransferase 2 have opposite atherosclerotic potential. Circ Res. 2004; 95: 998–1004.LinkGoogle Scholar25 Kusunoki J, Hansoty DK, Aragane K, Fallon JT, Badimon JJ, Fisher EA. Acyl-CoA:cholesterol acyltransferase inhibition reduces atherosclerosis in apolipoprotein E–deficient mice. Circulation. 2001; 103: 2604–2609.CrossrefMedlineGoogle Scholar26 Azuma Y, Date K, Ohno K, Matsushiro S, Nobuhara Y, Yamada T. NTE-122, an acyl-coa:cholesterol acyltransferase inhibitor, prevents the progression of atherogenesis in cholesterol-fed rabbits. Jpn J Pharmacol. 2001; 86: 120–123.CrossrefMedlineGoogle Scholar27 Aragane K, Kojima K, Fujinami K, Kamei J, Kusunoki J. Effect of F-1394, an acyl-CoA:cholesterol acyltransferase inhibitor, on atherosclerosis induced by high cholesterol diet in rabbits. Atherosclerosis. 2001; 158: 139–145.CrossrefMedlineGoogle Scholar28 Tardif JC, Gregoire J, L'Allier PL, Anderson TJ, Bertrand O, Reeves F, Title LM, Alfonso F, Schampaert E, Hassan A, McLain R, Pressler ML, Ibrahim R, Lesperance J, Blue J, Heinonen T, Rodes-Cabau J. Effects of the acyl coenzyme A:cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions. Circulation. 2004; 110: 3372–3377.LinkGoogle Scholar29 Crooke RM, Graham MJ, Lemonidis KM, Whipple CP, Koo S, Perera RJ. An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis. J Lipid Res. 2005; 46: 872–884.CrossrefMedlineGoogle Scholar30 Parini P, Davis M, Lada AT, Erickson SK, Wright TL, Gustafsson U, Sahlin S, Einarsson C, Eriksson M, Angelin B, Tomoda H, Omura S, Willingham MC, Rudel LL. ACAT2 is localized to hepatocytes and is the major cholesterol-esterifying enzyme in human liver. Circulation. 2004; 110: 2017–2023.LinkGoogle Scholar31 Chang CCY, Sakashita N, Ornvold K, Lee O, Chang ET, Dong R, Lin S, Lee C-YG, Strom SC, Kashyap R, Fung JJ, Farese RV Jr, Patoiseau J-F, Delhon A, Chang TY. Immunological quantitation and localization of ACAT-1 and ACAT-2 in human liver and small intestine. J Biol Chem. 2000; 275: 28083–28092.CrossrefMedlineGoogle Scholar32 Sakashita N, Miyazaki A, Chang CC, Chang TY, Kiyota E, Satoh M, Komohara Y, Morganelli PM, Horiuchi S, Takeya M. Acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) is induced in monocyte-derived macrophages: In vivo and in vitro studies. Lab Invest. 2003; 83: 1569–1581.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Bhattacharjee P, Rutland N and Iyer M (2022) Targeting Sterol O -Acyltransferase/Acyl-CoA:Cholesterol Acyltransferase (ACAT): A Perspective on Small-Molecule Inhibitors and Their Therapeutic Potential , Journal of Medicinal Chemistry, 10.1021/acs.jmedchem.2c01265, 65:24, (16062-16098), Online publication date: 22-Dec-2022. Hai Q and Smith J (2021) Acyl-Coenzyme A: Cholesterol Acyltransferase (ACAT) in Cholesterol Metabolism: From Its Discovery to Clinical Trials and the Genomics Era, Metabolites, 10.3390/metabo11080543, 11:8, (543) Wang D, Yang Y, Lei Y, Tzvetkov N, Liu X, Yeung A, Xu S, Atanasov A and Ma Q (2019) Targeting Foam Cell Formation in Atherosclerosis: Therapeutic Potential of Natural Products, Pharmacological Reviews, 10.1124/pr.118.017178, 71:4, (596-670), Online publication date: 1-Oct-2019. Parish E and Grainger W (2017) 4 Chemistry of Waxes and Sterols Food Lipids, 10.1201/9781315151854-5, (109-130), Online publication date: 23-Mar-2017. Saadane A, Mast N, Dao T, Ahmad B and Pikuleva I (2016) Retinal Hypercholesterolemia Triggers Cholesterol Accumulation and Esterification in Photoreceptor Cells, Journal of Biological Chemistry, 10.1074/jbc.M116.744656, 291:39, (20427-20439), Online publication date: 1-Sep-2016. Ma Z, Chao H, Turdi H, Hangeland J, Friends T, Kopcho L, Lawrence R and Cheng D (2016) Characterization of monoacylglycerol acyltransferase 2 inhibitors by a novel probe in binding assays, Analytical Biochemistry, 10.1016/j.ab.2016.02.012, 501, (48-55), Online publication date: 1-May-2016. Boucher P and Vogel H (2016) Influence of Lipid Metabolism Drug Discovery and Evaluation: Pharmacological Assays, 10.1007/978-3-319-05392-9_47, (2227-2246), . Lopez A, Chuang J, Posey K, Ohshiro T, Tomoda H, Rudel L and Turley S (2015) PRD125, a Potent and Selective Inhibitor of Sterol O -Acyltransferase 2 Markedly Reduces Hepatic Cholesteryl Ester Accumulation and Improves Liver Function in Lysosomal Acid Lipase-Deficient Mice , Journal of Pharmacology and Experimental Therapeutics, 10.1124/jpet.115.227207, 355:2, (159-167), Online publication date: 1-Nov-2015. Lee S, Li J, Tai J, Ratliff T, Park K and Cheng J (2015) Avasimibe Encapsulated in Human Serum Albumin Blocks Cholesterol Esterification for Selective Cancer Treatment, ACS Nano, 10.1021/nn504025a, 9:3, (2420-2432), Online publication date: 24-Mar-2015. Matsuo K, Akakabe Y, Kitamura Y, Shimoda Y, Ono K, Ueyama T, Matoba S, Yamada H, Hatakeyama K, Asada Y, Emoto N and Ikeda K (2015) Loss of Apoptosis Regulator through Modulating IAP Expression (ARIA) Protects Blood Vessels from Atherosclerosis, Journal of Biological Chemistry, 10.1074/jbc.M114.605287, 290:6, (3784-3792), Online publication date: 1-Feb-2015. Boucher P and Vogel H (2015) Influence of Lipid Metabolism Drug Discovery and Evaluation: Pharmacological Assays, 10.1007/978-3-642-27728-3_47-1, (1-22), . Lopez A, Posey K and Turley S (2014) Deletion of sterol O-acyltransferase 2 (SOAT2) function in mice deficient in lysosomal acid lipase (LAL) dramatically reduces esterified cholesterol sequestration in the small intestine and liver, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2014.10.063, 454:1, (162-166), Online publication date: 1-Nov-2014. Wang Y, Yi X, Ghanam K, Zhang S, Zhao T and Zhu X (2014) Berberine decreases cholesterol levels in rats through multiple mechanisms, including inhibition of cholesterol absorption, Metabolism, 10.1016/j.metabol.2014.05.013, 63:9, (1167-1177), Online publication date: 1-Sep-2014. Ohshiro T and Tomoda H (2013) DISCOVERY AND DEVELOPMENT OF ISOZYME-SELECTIVE INHIBITORS INVOLVED IN LIPID METABOLISM Enzyme Technologies, 10.1002/9781118739907.ch2, (55-80) Stoekenbroek R, Kastelein J and Hovingh G (2013) Recent failures in antiatherosclerotic drug development, Current Opinion in Lipidology, 10.1097/MOL.0000000000000024, 24:6, (459-466), Online publication date: 1-Dec-2013. Trenin A (2013) Microbial metabolites inhibiting sterol biosynthesis: Their chemical diversity and characteristics of the mechanism of action, Russian Journal of Bioorganic Chemistry, 10.1134/S1068162013060095, 39:6, (565-587), Online publication date: 1-Nov-2013. Floettmann J, Buckett L, Turnbull A, Smith T, Hallberg C, Birch A, Lees D and Jones H (2013) ACAT-selective and Nonselective DGAT1 Inhibition, Toxicologic Pathology, 10.1177/0192623313477753, 41:7, (941-950), Online publication date: 1-Oct-2013. Allian-Sauer M and Falko J (2014) New treatments on the horizon for familial hypercholesterolemia, Expert Review of Cardiovascular Therapy, 10.1586/erc.12.112, 10:10, (1227-1237), Online publication date: 1-Oct-2012. Choi S, Lee M, Choi J and Kim Y (2012) 2,3,22,23-Tetrahydroxyl-2,6,10,15,19,23-hexamethyl-6,10,14,18-tetracosatetraene, an Acyclic Triterpenoid Isolated from the Seeds of Alpinia katsumadai, Inhibits Acyl-CoA : Cholesterol Acyltransferase Activity, Biological and Pharmaceutical Bulletin, 10.1248/bpb.b12-00617, 35:11, (2092-2096), . Ohshiro T, Matsuda D, Sakai K, Degirolamo C, Yagyu H, Rudel L, Ōmura S, Ishibashi S and Tomoda H (2011) Pyripyropene A, an Acyl–Coenzyme A:Cholesterol Acyltransferase 2–Selective Inhibitor, Attenuates Hypercholesterolemia and Atherosclerosis in Murine Models of Hyperlipidemia, Arteriosclerosis, Thrombosis, and Vascular Biology, 31:5, (1108-1115), Online publication date: 1-May-2011. Bass T (2010) DGAT out of the bag, Science-Business eXchange, 10.1038/scibx.2010.1253, 3:42, (1253-1253), Online publication date: 1-Oct-2010. Veng L, Savage M, Barrow J and Zerbinatti C (2010) Non‐amyloid Approaches To Alzheimer's Disease Burger's Medicinal Chemistry and Drug Discovery, 10.1002/0471266949.bmc253, (405-446) Matsuda D, Ohshiro T, Ohba M, Jiang W, Hong B, Si S and Tomoda H (2009) The Molecular Target of Rubimaillin in the Inhibition of Lipid Droplet Accumulation in Macrophages, Biological and Pharmaceutical Bulletin, 10.1248/bpb.32.1317, 32:8, (1317-1320), . Tiwari R, Singh V and Barthwal M (2008) Macrophages: An elusive yet emerging therapeutic target of atherosclerosis, Medicinal Research Reviews, 10.1002/med.20118, 28:4, (483-544), Online publication date: 1-Jul-2008. El Harchaoui K, Akdim F, Stroes E, Trip M and Kastelein J (2008) Current and Future Pharmacologic Options for the Management of Patients Unable to Achieve Low-Density Lipoprotein-Cholesterol Goals with Statins, American Journal of Cardiovascular Drugs, 10.2165/00129784-200808040-00003, 8:4, (233-242), . Matsuda D, Ohte S, Ohshiro T, Jiang W, Rudel L, Hong B, Si S and Tomoda H (2008) Molecular Target of Piperine in the Inhibition of Lipid Droplet Accumulation in Macrophages, Biological and Pharmaceutical Bulletin, 10.1248/bpb.31.1063, 31:6, (1063-1066), . Spector A and Haynes W (2007) LDL Cholesteryl Oleate, Arteriosclerosis, Thrombosis, and Vascular Biology, 27:6, (1228-1230), Online publication date: 1-Jun-2007. Burnett J and Huff M (2006) Cholesterol absorption inhibitors as a therapeutic option for hypercholesterolaemia, Expert Opinion on Investigational Drugs, 10.1517/13543784.15.11.1337, 15:11, (1337-1351), Online publication date: 1-Nov-2006. August 2006Vol 26, Issue 8 Advertisement Article InformationMetrics https://doi.org/10.1161/01.ATV.0000227511.35456.90PMID: 16857957 Originally publishedAugust 1, 2006 PDF download Advertisement
Referência(s)