Inhibition of acyl coenzyme a-cholesterol acyltransferase: A possible treatment of atherosclerosis?

Heinonen, Therèse

doi:10.1007/s11883-002-0064-9

Cited by 19 publications

(12 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Apolipoprotein E knockout mice spontaneously developed atherosclerosis and constitute a model of atherosclerosis. On this model, it has been reported that a partial inhibition of ACAT activity is sufficient to induce a regression of the atheromatous lesion without producing side effects (Delsing et al, 2001;Kusunoki et al, 2001;Heinonen, 2002). These data suggest that a partial inhibition of ACAT might be sufficient for atheroprotection in humans.…”

Section: Abbreviationsmentioning

confidence: 77%

Tamoxifen Is a Potent Inhibitor of Cholesterol Esterification and Prevents the Formation of Foam Cells

Médina

Payré²,

Bernad³

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Tamoxifen is a selective estrogen receptor modulator (SERM) used for the treatment and prevention of breast cancer. Tamoxifen has been reported to protect against the progression of coronary artery diseases in human and different atherosclerosis animal models by blocking the appearance of the atheromatous plaque. However, the molecular mechanism of this effect remains unknown. Acyl-CoA:cholesterol acyl transferase (ACAT) catalyzes the biosynthesis of cholesteryl esters, which are the major lipids found in the atheromatous plaque. In this paper we have tested whether ACAT might be inhibited by tamoxifen. We show, using molecular modeling, that tamoxifen displays three-dimensional structural homology with Sah 58-035 (3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide), a prototypical inhibitor of ACAT. We report that tamoxifen inhibits ACAT in a concentration-dependent manner on rat liver microsomal extract. We show that the presence on estrogen receptor ligands of a backbone isosteric to the diphenyl ethane backbone of Sah 58-035 constitutes a pharmacophore for ACAT inhibition. More importantly, tamoxifen was able to inhibit ACAT on intact macrophages stimulated with acetylated low-density lipoproteins and blocked the formation of foam cells, a step that precedes the formation of the atheromatous plaque. This work constitutes the first evidence that tamoxifen is an inhibitor of ACAT and foam cell formation at therapeutic doses and that this may account for its atheroprotective action.

show abstract

Section: Abbreviationsmentioning

confidence: 77%

Tamoxifen Is a Potent Inhibitor of Cholesterol Esterification and Prevents the Formation of Foam Cells

Médina

Payré²,

Bernad³

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…Thus, decrease in the CE burden of the plaque is a potentially promising strategy for reducing lesion growth and rupture explored previously by ACAT1 inhibition (39) and overexpression of adipose tissue HSL (40). The data presented here suggest that approaches to enhance expression or up-regulation of CEH in macrophages could provide a new therapeutic strategy to attenuate the CE burden of plaque-associated foam cells.…”

Section: Discussionmentioning

confidence: 99%

Mobilization of cytoplasmic CE droplets by overexpression of human macrophage cholesteryl ester hydrolase

Ghosh

Clair

Rudel

2003

Journal of Lipid Research

View full text Add to dashboard Cite

The obligatory first step in the removal of cholesterol from foam cells is the hydrolysis of stored cholesteryl esters (CEs) to release free cholesterol (FC). Neutral cholesteryl ester hydrolase (CEH) catalyzes this hydrolysis, and limiting levels of CEH could play a role in determining the susceptibility to atherosclerosis. We have recently reported the first identification and cloning of cDNA for human macrophage CEH. In the present study, we tested the hypothesis that systematically varied levels of overexpression of human macrophage CEH results in a proportional degree of reduction in cellular CE content in a cell system with known and reproducible amounts of CE accumulation. CEH expression was confirmed by demonstrating the presence of CEH mRNA and protein with an increase in CEH activity. A significant reduction in intracellular lipid droplets was observed in CEH-expressing cells, together with a decrease in cellular CE mass and a 2-fold increase in FC efflux. These results demonstrate that when human macrophage CEH is expressed in lipid-laden cells, hydrolysis and mobilization of CE (stored as lipid droplets) occur. These data establish the possibility that increased CE hydrolysis, mediated by CEH up-regulation, could represent an important mechanism to reduce the cholesterol burden of foam cells. Atherosclerotic lesions begin as fatty streaks resulting from the recruitment of blood monocytes to the arterial wall, where they differentiate into macrophages and ultimately accumulate cholesterol from the uptake of modified cholesteryl ester (CE)-rich lipoproteins. Unregulated uptake of modified forms of LDL (oxidized, aggregated, etc.) via scavenger receptors, e.g., scavenger receptor A and CD36, leads to the development of macrophage "foam cells" that contain massive amounts of cytoplasmic CE inclusions. Lipoprotein-associated CEs are first hydrolyzed in the lysosomes with the resulting free cholesterol (FC) being transferred out of the lysosome. The FC content of cells is maintained under tight control in order to prevent excessive enrichment with FC of the plasma membranes, which can alter membrane function (1). Two processes working in tandem are involved in maintaining the homeostatic balance between intracellular FC and CEs: esterification of excess FC by acyl CoA: cholesterol acyltransferase (1) (ACAT1), and hydrolysis of CE by a neutral cholesteryl ester hydrolase (CEH). This "futile" cycle of CE and hydrolysis is known as the CE cycle and serves to maintain appropriate FC availability for cell membranes (2).Efficient cholesterol efflux from macrophages is critical for the prevention of foam cell formation and for subsequent protection against atherosclerosis. Because there is no significant release of intact CE from cells, including macrophages, for efflux to occur, CE must first be hydrolyzed to FC. FC leaves the cell by being picked up by one of several cholesterol acceptors in the extracellular space. Ultimately, FC is transferred into HDL, where much of it is esterified by lecithin:chol...

show abstract

“…The enzyme acyl coenzyme A:cholesterol acyltransferase (ACAT) has been an intriguing target for potential pharmacological intervention. 1 ACAT is found in many tissue types that require the storage of cholesterol, including intestinal and hepatic tissue, as well as arterial macrophages. [2][3][4][5] Cholesterol ester accumulation in macrophages indeed requires the action of ACAT, thereby promoting foam cell formation.…”

mentioning

confidence: 99%

Effects of the Acyl Coenzyme A:Cholesterol Acyltransferase Inhibitor Avasimibe on Human Atherosclerotic Lesions

et al. 2004

View full text Add to dashboard Cite

Background-Inhibition of the acyl coenzyme A:cholesterol acyltransferase (ACAT) enzyme may prevent excess accumulation of cholesteryl esters in macrophages. The ACAT inhibitor avasimibe was shown to reduce experimental atherosclerosis. This study was designed to investigate the effects of avasimibe on human coronary atherosclerosis. Methods and Results-This randomized, double-blind, placebo-controlled trial assessed the effects of avasimibe at dosages of 50, 250, and 750 mg QD on the progression of coronary atherosclerosis as assessed by intravascular ultrasound (IVUS). All patients received background lipid-lowering therapy if necessary to reach a target baseline LDL level Ͻ125 mg/dL (3.2 mmol/L). IVUS and coronary angiography were performed at baseline and repeated after up to 24 months of treatment. Approximately equal percentages of patients across groups received concurrent statin therapy (87% to 89%). The mean total plaque volume at baseline was Ϸ200 mm 3 , and the least squares mean change at end of treatment was 0.7 mm 3 for placebo and 7.7, 4.1, and 4.8 mm 3 for the avasimibe 50, 250, and 750 mg groups, respectively (adjusted Pϭ0.17 [unadjusted Pϭ0.057], 0.37, and 0.37, respectively). Percent atheroma volume increased by 0.4% with placebo and by 0.7%, 0.8%, and 1.0% in the respective avasimibe groups (PϭNS). LDL cholesterol increased during the study by 1.7% with placebo but by 7.8%, 9.1%, and 10.9% in the respective avasimibe groups (PϽ0.05 in all groups). Conclusions-Avasimibe did not favorably alter coronary atherosclerosis as assessed by IVUS. This ACAT inhibitor also caused a mild increase in

show abstract

Inhibition of acyl coenzyme a-cholesterol acyltransferase: A possible treatment of atherosclerosis?

Cited by 19 publications

References 45 publications

Tamoxifen Is a Potent Inhibitor of Cholesterol Esterification and Prevents the Formation of Foam Cells

Tamoxifen Is a Potent Inhibitor of Cholesterol Esterification and Prevents the Formation of Foam Cells

Mobilization of cytoplasmic CE droplets by overexpression of human macrophage cholesteryl ester hydrolase

Effects of the Acyl Coenzyme A:Cholesterol Acyltransferase Inhibitor Avasimibe on Human Atherosclerotic Lesions

Contact Info

Product

Resources

About