| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Acute inflammation, acute phase serum amyloid A and cholesterol metabolism in the mouse Lindhorst, E., D. Young, et al. (1997), Biochim Biophys Acta 1339(1): 143-54. Abstract: Acute inflammation results in a profound change in the apolipoprotein composition of high density lipoprotein (HDL). Several isoforms of the serum amyloid A (SAA) family, SAA1 and SAA2, become major components of HDL. This structural relationship has suggested that acute phase SAA plays some as yet unidentified role in HDL function, possibly related to cholesterol transport, during the course of acute inflammation. Using subcutaneous AgNO3 to induce a sterile abscess changes in plasma cholesterol and SAA were monitored over the subsequent 144 h. Total plasma cholesterol began to increase within 12 h of the induction of inflammation and reached a peak in 24 h. Thereafter its plasma levels fell returning to normal values by 96-120 h. The bulk of the increase in plasma cholesterol was found in the free cholesterol fraction of HDL. This pattern of cholesterol increase corresponds to the established temporal changes for acute phase SAA (AP-SAA). AP-SAA levels increased within 8 h of the induction of inflammation and reached a peak at 24 h. They began to decrease by 48 h with small quantites still present 120 h later. In concert, but inversely, with the changes in AP-SAA the apoA-I, apoA-II, and apo-E, content of HDL decreased during the AP-SAA increases and increased as AP-SAA levels fell. The plasma appearance of cholesterol from the periphery, and central parts of the inflammatory site was assessed by the use of radiolabelled cholesterol. The peripherally placed cholesterol rapidly reached a peak plasma concentration within 24 h of injection. Cholesterol placed in the central part of the sterile abscess, a site relatively inaccessible to the vasculature required 48 h to reach its peak and was 5-times lower than that placed peripherally. The influence of AP-SAA on neutral cholesterol ester hydrolase (nCEH) activity in mouse liver homogenates, mouse peritoneal macrophage homogenates, and a purified porcine pancreatic enzyme with nCEH activity was also assessed. Following optimization with regard to pH, bile salt concentration, protein concentration and incubation time, mouse peritoneal macrophages had a significantly higher nCEH specific activity than that found in liver (7-8 fold). Purified AP-SAA, assessed over a concentration range of 0-10 microg/ml, enhanced nCEH activity at concentrations above 2 microg/ml. The nCEH activity, regardless of its source, increased by 3-7 fold in the presence of AP-SAA. Equivalent concentrations of apolipoprotein A-I (apo A-I) and bovine serum albumin (BSA) failed to alter the activity of nCEH. The effect of AP-SAA on a purified form of nCEH suggests that AP-SAA may have a direct effect on the activity of this enzyme. The temporal correlation of circulating AP-SAA and plasma cholesterol and the significant stimulation of nCEH by AP-SAA (but not apoA-I or BSA) provides further evidence that AP-SAA plays a role in cholesterol metabolism during the course of acute inflammation. |
| Acute pancreatitis and stomach wall necrosis caused by cholesterol embolisms Scheppach, W., M. Teschner, et al. (1993), Dtsch Med Wochenschr 118(1-2): 13-8. Abstract: A 60-year-old man was hospitalized because of a sudden onset of severe pain in the epigastrium and haematemesis. Acute pancreatitis was diagnosed on the basis of an increased serum amylase concentration (642 U/l). Abdominal ultrasound and computed tomography demonstrated a necrotic zone with central liquefaction in the tail of the pancreas adjoining the stomach wall. Gastroscopy revealed as source of the bleeding an extensive mucosal necrosis at the greater curvature of the stomach. At laparotomy, partial resection of the pancreas, gastrectomy and splenectomy were performed. Histological examination of the resected specimens showed multiple cholesterol emboli in the small arteries of the pancreas and the gastric submucosa. |
| Acute pancreatitis in the rat following experimental microembolism with cholesterol crystals Freiburghaus, A. U., F. Redha, et al. (1992), Helv Chir Acta 58(5): 611-5. Abstract: Several case reports exist which demonstrate cholesterol crystals to be the cause of acute pancreatitis in humans. The crystals have been found intravascularly in the pancreas and at least in one case the origin of the crystals was known. We have undertaken to experimentally reproduce this pathogenetic mechanism in the rat. 30 rats were subjected to the following procedures: under anaesthesia the splenic artery was distally ligated and proximally cannulated; 16 control animals were injected via the cannula with saline (8 rats), particle free cholesterol saturated physiologic saline (3 rats) or nothing (5 rats). 14 rats were injected with ca. 400 microliters of a dilute suspension of cholesterol crystals of 5-40 microns diameter in cholesterol saturated physiologic saline. The abdomen was closed and after 24 h all animals were killed. Acute pancreatitis was diagnosed in all animals that received cholesterol microcrystals and in none of the controls. The diagnosis was based on macroscopic and histological findings. Acute pancreatitis was of focal, disseminated, necrotic type with oedema and moderate haemorrhage and fat necrosis. Only those parts of the pancreas were affected which were supplied by branches of the distal splenic artery used for retrograde injections of cholesterol crystals. This model supports the notion that microembolic or microthrombotic events play a pivotal role in the pathogenesis of spontaneous acute pancreatitis. |
| Acute phase serum amyloid A, cholesterol metabolism, and cardiovascular disease Kisilevsky, R. and S. P. Tam (2002), Pediatr Pathol Mol Med 21(3): 291-305. Abstract: Our review examines the nature of serum amyloid A, its isoforms and, their structure, the manner of induction of the acute phase forms and argument for and against their possible physiological function (s). In this context, the possible role of serum amyloid A as a prognostic indicator of unstable angina and its significance in relation to cardiovascular disease is discussed. |
| Acute tubular injury causes dysregulation of cellular cholesterol transport proteins Zager, R. A., A. C. Johnson, et al. (2003), Am J Pathol 163(1): 313-20. Abstract: Acute renal injury causes accumulation of free and esterified cholesterol (FC, CE) in proximal tubules, mediated, at least in part, by increased cholesterol synthesis. Normally, this would trigger compensatory mechanisms such as increased efflux and decreased influx to limit or reverse the cholesterol overload state. This study sought to determine the integrity of these compensatory pathways following acute renal damage. Rhabdomyolysis-induced acute renal failure was induced in mice by glycerol injection. Normal mice served as controls. After 18 hours, BUN levels and renal cortical FC/CE content were determined. Expression of ABCA-1 and SR-B1 (cholesterol efflux proteins) were assessed by Western blot. Renal cortical LDL receptor (LDL-R; a cholesterol importer) regulation was gauged by quantifying its mRNA. To obtain proximal tubule cell-specific data, the impact of oxidant (Fe) stress on cultured HK-2 cell LDL-R, SR-B1, and ABCA-1 proteins and their mRNAs (versus controls) was assessed. Glycerol evoked marked azotemia and striking FC/CE increments (44%, 384%, respectively). Paradoxically, renal cortical SR-B1 and ABCA-1 protein reductions and LDL-R mRNA increments resulted. Fe-induced injury suppressed HK-2 cell SR-B1, ABCA-1, and their mRNAs. LDL-R protein rose with the in vitro Fe challenge. Renal tubular cell injury causes dysregulation of SR-B1, ABCA-1, and LDL-R protein expression, changes which should contribute to a cholesterol overload state. Reductions in HK-2 cell SR-B1 and ABCA-1 mRNAs and increases in renal cortical LDL-R mRNA imply that this dysregulation reflects, at least in part, altered genomic/transcriptional events. |
| Acute uremia after renal cholesterol embolism Cintin, C., A. H. Nielsen, et al. (1992), Ugeskr Laeger 154(26): 1848-9. Abstract: A case of acute uraemia caused by cholesterol emboli in the kidneys in a sixty-six year old male with arteriosclerosis is presented. No effective treatment is available, but recognizing the condition may save the patient from otherwise time-consuming extensive diagnostic programmes. |
| Acyl chain unsaturation modulates distribution of lecithin molecular species between mixed micelles and vesicles in model bile. Implications for particle structure and metastable cholesterol solubilities Cohen, D. E. and M. C. Carey (1991), J Lipid Res 32(8): 1291-302. Abstract: We determined the distribution of lecithin molecular species between vesicles and mixed micelles in cholesterol super-saturated model biles (molar taurocholate-lecithin-cholesterol ratio 67:23:10, 3 g/dl, 0.15 M NaCl, pH approximately 6-7) that contained equimolar synthetic lecithin mixtures or egg yolk or soybean lecithins. After apparent equilibration (48 h), biles were fractionated by Superose 6 gel filtration chromatography at 20 degrees C, and lecithin molecular species in the vesicle and mixed micellar fractions were quantified as benzoyl diacylglycerides by high performance liquid chromatography. With binary lecithin mixtures, vesicles were enriched with lecithins containing the most saturated sn-1 or sn-2 chains by as much as 2.4-fold whereas mixed micelles were enriched in the more unsaturated lecithins. Vesicles isolated from model biles composed of egg yolk (primarily sn-1 16:0 and 18:0 acyl chains) or soy bean (mixed saturated and unsaturated sn-1 acyl chains) lecithins were selectively enriched (6.5-76%) in lecithins with saturated sn-1 acyl chains whereas mixed micelles were enriched with lecithins composed of either sn-1 18:1, 18:2, and 18:3 unsaturated or sn-2 20:4, 22:4, and 22:6 polyunsaturated chains. Gel filtration, lipid analysis, and quasielastic light scattering revealed that apparent micellar cholesterol solubilities and metastable vesicle cholesterol/lecithin molar ratios were as much as 60% and 100% higher, respectively, in biles composed of unsaturated lecithins. Acyl chain packing constraints imposed by distinctly different particle geometries most likely explain the asymmetric distribution of lecithin molecular species between vesicles and mixed micelles in model bile as well as the variations in apparent micellar cholesterol solubilities and vesicle cholesterol/lecithin molar ratios.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Acyl CoA: cholesterol acyltransferase activity in the yolk sac membrane of the chick embryo Shand, J. H., D. W. West, et al. (1992), Biochem Soc Trans 20(4): 340S. |
| Acyl CoA:cholesterol acyltransferase (ACAT) inhibitors: synthesis and structure-activity relationship studies of a new series of trisubstituted imidazoles Higley, C. A., R. G. Wilde, et al. (1994), J Med Chem 37(21): 3511-22. Abstract: A series of 4,5-diaryl-2-(substituted thio)-1H-imidazoles has been synthesized and demonstrated to be potent inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). The design, synthesis, and structure-activity relationships for this series are reported herein. One of the compounds from this series, N'-(2,4-difluorophenyl)-N-5-(4,5-diaryl-1H-imidazol-2- yl)thiopentyl-N-heptylurea (DuP 128), was selected for development as an intestinally active ACAT inhibitor. DuP 128 is a potent ACAT inhibitor in vitro and in vivo, inhibiting ACAT in rat hepatic microsomes with an IC50 = 10 nM and possessing potent antihypercholesterolemic activity in vivo. |
| Acyl coenzyme A: cholesterol acyltransferase inhibition and hepatic apolipoprotein B secretion Burnett, J. R., L. J. Wilcox, et al. (1999), Clin Chim Acta 286(1-2): 231-42. Abstract: Acyl coenzyme A: cholesterol acyltransferase (ACAT) is postulated to play a role in hepatic and intestinal lipoprotein secretion. There is accumulating evidence, both in vitro and in vivo, that cholesterol and/or cholesteryl ester availability can regulate hepatic VLDL secretion. How ACAT inhibition regulates the assembly and secretion of apolipoprotein (apo) B containing lipoproteins within the hepatocyte has not been clearly established. ApoB kinetic studies performed in animals indicate that reduction in VLDL apoB secretion is an important mechanism whereby ACAT inhibitors decrease the plasma concentrations of these lipoproteins. However, in cultured hepatocytes, the effect of ACAT inhibition on apoB secretion has been inconsistent. Recent evidence has suggested the existence of more than one ACAT enzyme in mammals, which has culminated in the recent cloning of ACAT2. ACAT1 and ACAT2 respond differently to ACAT inhibitors of differing structures and classes. ACAT2 is present in the liver and intestine, the sites of apoB containing lipoprotein secretion and may represent the enzyme responsible for generating cholesteryl esters destined for lipoprotein assembly and secretion. |
| Acyl coenzyme A:cholesterol acyltransferase inhibition: potential atherosclerosis therapy or springboard for other discoveries? Heinonen, T. M. (2002), Expert Opin Investig Drugs 11(11): 1519-27. Abstract: Cholesterol is an essential building block without which humans and other animals could not exist. As with most necessities, under certain conditions, excess can sharply tip the scale and lead to an unfavourable outcome. Excess cholesterol is stored as cholesteryl ester through an esterification process regulated in part by acyl coenzyme A:cholesterol acyltransferase (ACAT). ACAT is found in many tissue types which require the storage of cholesterol. Most notably, for cardiovascular disease ACAT activity is significant in intestinal and hepatic tissue and arterial macrophages. Several ACAT inhibitors have been investigated for their potential to favourably alter serum lipoprotein levels by blocking intestinal absorption, hepatic inhibition and/or slowing the progression of atherosclerosis through a non-lipid arterial inhibition. Recent evaluations of ACAT and ACAT inhibitors have provided some insight into the therapeutic potential and risks of ACAT inhibition as a means of treating atherosclerosis. |
| Acylation of 3beta-(2-hydroxyethoxy)cholest-5-ene in the presence of lecithin:cholesterol acyltransferase from blood plasma Maliugin, A. V. and A. Misharin (1997), Bioorg Khim 23(1): 75-7. Abstract: 3 beta-(2-Hydroxyethoxy)cholest-5-ene in the composition of the micellar complexes with apolipoprotein A1 and palmitoyloleoylphosphatidylcholine was acylated in the presence of lecithin-cholesterol acyltransferase from human plasma. The initial rate of acylation was 6-8 times lower than the rate of cholesterol acylation under the same conditions. The presence of 3 beta-(2-hydroxyethoxy)cholest-5-ene did not affect the rate of the enzymic acylation of cholesterol. |
| Acylation-stimulatory activity in hyperapobetalipoproteinemic fibroblasts: enhanced cholesterol esterification with another serum basic protein, BP II Kwiterovich, P., Jr., M. Motevalli, et al. (1990), Proc Natl Acad Sci U S A 87(22): 8980-4. Abstract: Cultured fibroblasts from patients with familial hyperapobetalipoproteinemia (hyperapoB) were used to determine if a defect in lipid metabolism was present. Three basic proteins (BP I, BP II, and BP III) were isolated from normal human serum by preparative isoelectric focusing, preparative SDS/PAGE, and reversed-phase HPLC. The Mr and pI values of these proteins were 14,000 and 9.10 for BP I, 27,500 and 8.48 for BP II, and 55,000 and 8.73 for BP III. These proteins differed significantly in their content of arginine, cysteine, proline, histidine, serine, and methionine. BP I appears to be the same protein as acylation-stimulating protein, but BP II and BP III appeared different from acylation-stimulating protein and other lipid carrier proteins. BP I, BP II, and BP III stimulated the incorporation of 14Coleate into lipid esters in normal fibroblasts, an effect that was time and concentration dependent. In hyperapoB cells, BP II markedly increased (up to 9-fold) the incorporation of 14Coleate into cholesteryl ester compared with that in normal cells; in addition, there was a 50% decrease in the stimulation of triglyceride acylation and cholesterol esterification with BP I. No difference between normal and hyperapoB cells was observed with BP III. In summary, the identification of another serum basic protein, BP II, led to the elucidation of another cellular defect in hyperapoB fibroblasts, enhanced cholesterol esterification, which may be related to the precocious atherosclerosis and abnormal lipoprotein metabolism seen in hyperapoB. |
| Acyl-CoA binding protein (ACBP) regulates acyl-CoA:cholesterol acyltransferase (ACAT) in human mononuclear phagocytes Kerkhoff, C., M. Beuck, et al. (1997), Biochim Biophys Acta 1346(2): 163-72. Abstract: It is demonstrated that the acyl-CoA:cholesterol acyltransferase (ACAT) enzyme activity in rough endoplasmatic reticulum membranes is regulated by the acyl-CoA binding protein (ACBP). The ACAT activity is strongly inhibited by different ACBP/oleoyl-CoA complexes depending from the molar ratio of protein and fatty acid-CoA. Other lipid binding proteins such as bovine serum albumin and the liver fatty acid binding protein do not show any effects on ACAT activity. In addition, we can show that cholesterol loading with acetylated low density lipoproteins does not lead to an increase of the ACBP mRNA level. Consequently, the increase of the intracellular concentration of fatty acids because of the cholesteryl ester accumulation renders ACAT more active for cholesterol esterification. In binding studies we have characterized binding sites on microsomal membranes for the ACAT substrate oleoyl-CoA and the ACAT inhibitor diazepam. Diazepam competes with oleoyl-CoA and vice versa for its binding to microsomal membranes. This common binding site is suggested to be responsible for the transfer from ACBP-bound oleoyl-CoA to ACAT and, therefore, to be essential for the microsomal cholesterol esterification. |
| Acyl-CoA: cholesterol acyltransferase in HT 29 cell subpopulations. Defect of activity in the undifferentiated cells Viallard, V., C. Lacombe, et al. (1991), Biochim Biophys Acta 1085(2): 265-71. Abstract: The ACAT activity was studied on different subpopulations deriving from HT29 cells, a human colon carcinoma cell line. Grown on standard medium (25 mM glucose), about 95% of these cells are undifferentiated (G + cells). From this heterogeneous population, differentiated cells were selected by glucose deprivation and grown either on medium without glucose (G - cells) or in standard medium containing 25 mM glucose (G-Rev cells). The G- and G-Rev cells have the features of differentiated small intestine cells. The two types of differentiated cells (G- and G-Rev) exhibited similar ACAT activities and the kinetic characteristics of the enzyme were also similar. A time-course study showed increasing activity during the exponential phase and a decrease just after confluency. It was possible to stimulate the enzyme by micellar or lipoprotein cholesterol. In contrast, the ACAT activity was hardly detectable in undifferentiated G + cells. In addition, all the experimental conditions known to stimulate ACAT activity, and confirmed in the differentiated HT29 cells, were inefficient in the undifferentiated G + cells. Therefore, the different models derived from HT29 cells provide the opportunity to study cholesterol esterification as well as the consequences of its aberrances in intestinal cells. |
| Acyl-CoA:cholesterol acyltransferase inhibition reduces atherosclerosis in apolipoprotein E-deficient mice Kusunoki, J., D. K. Hansoty, et al. (2001), Circulation 103(21): 2604-9. Abstract: BACKGROUND:Acyl-COA:cholesterol acyltransferase (ACAT) converts cholesterol to cholesteryl esters. The form of ACAT in macrophages, ACAT1, contributes to foam cell formation in the arterial wall and the development of atherosclerosis. Recent studies in a mouse model of atherosclerosis (the apolipoprotein E apoE-deficient mouse), however, have suggested that complete deficiency of ACAT1 activity is not antiatherogenic, in part because of toxicity resulting from adverse effects on tissue cholesterol homeostasis. We have tested whether partial inhibition of ACAT1 and ACAT2 (expressed in liver and intestine) activities reduces atherosclerosis development in apoE-deficient mice and avoids toxicity. Methods and RESULTS:ApoE-deficient mice were maintained for 17 weeks on a Western-type diet without (control) or with the ACAT inhibitor F-1394 (effective against ACAT1 and ACAT2) at doses of either 300 (low) or 900 (high) mg/kg. Intimal lesion area at the aortic sinus in controls was 0.69+/-0.06 mm(2). F-1394 treatment significantly decreased lesional area by 39% (low) or 45% (high). F-1394 treatment also reduced lesional immunostaining for macrophages by 61% (low) or 83% (high). En face analysis showed that surface lipid staining in control aortas was 20.0+/-2.8%; F-1394 treatment reduced this by 46% (low) or 62% (high). There were no obvious signs of systemic or vessel wall toxicity associated with F-1394 treatment. CONCLUSIONS:Partial ACAT inhibition by F-1394 had antiatherogenic effects in apoE-deficient mice that were achieved without obvious toxicity. Partial ACAT inhibition may have therapeutic potential in the clinical treatment of atherosclerosis. |
| Acyl-CoA:cholesterol acyltransferase inhibitor avasimibe reduces atherosclerosis in addition to its cholesterol-lowering effect in ApoE*3-Leiden mice Delsing, D. J., E. H. Offerman, et al. (2001), Circulation 103(13): 1778-86. Abstract: BACKGROUND: The present study investigated whether the ACAT inhibitor avasimibe can reduce atherogenesis independently of its cholesterol-lowering effect in ApoE*3-Leiden mice. METHODS AND RESULTS: Two groups of 15 female ApoE*3-Leiden mice were put on a high-cholesterol (HC) diet; 1 group received 0.01% (wt/wt) avasimibe mixed into the diet. The HC diet resulted in a plasma cholesterol concentration of 18.7+/-2.6 mmol/L. Addition of avasimibe lowered plasma cholesterol by 56% to 8.1+/-1.2 mmol/L, caused mainly by a reduction of and composition change in VLDL and LDL. In a separate low-cholesterol (LC) control group, plasma cholesterol was titrated to a level comparable to that of the avasimibe group (10.3+/-1.4 mmol/L) by lowering the amount of dietary cholesterol. After 22 weeks of intervention, atherosclerosis in the aortic root area was quantified. Treatment with avasimibe resulted in a 92% reduction of lesion area compared with the HC control group. Compared with the LC control, avasimibe reduced lesion area by 78%. After correction for the slight difference in cholesterol exposure between the LC control and avasimibe groups, the effect of avasimibe on lesion area (73% reduction) remained highly significant. In addition, monocyte adherence to the endothelium, free cholesterol accumulation, and lesion severity were reduced by avasimibe treatment. CONCLUSIONS: Treatment with avasimibe potently lowered plasma cholesterol levels in ApoE*3-Leiden mice and considerably reduced atherosclerotic lesion area in addition to its cholesterol-lowering effect. Because monocyte adherence to the endothelium and lesion severity were also reduced by avasimibe, treatment with avasimibe may result in higher plaque stability and therefore a reduced risk of plaque rupture. |
| Acyl-coenzyme A: cholesterol- acyl-coenzyme A:1,2-diacylglycerol acyltransferase and phosphatidate phosphorylase activities in liver microsomes from nephrotic rats Agbedana, E. O., T. Yamamoto, et al. (1996), Afr J Med Med Sci 25(4): 365-71. Abstract: The lipid components of very low density lipoproteins (VLDL) were significantly elevated in the nephrotic rats. Also the nephrotic VLDL particles had a significantly higher ratio of surface lipids (FC + PL) to core lipids (TG + CE) probably indicating production of smaller sized VLDL in the nephrotic rats. Electron microscopy showed VLDL particles with a reduced mean size in the nephrotic rats. The activities of VLDL core lipid synthesizing enzymes were evaluated in experimental nephrotic syndrome. In addition, the effects of exogeneous cholesterol, 25-OH-cholesterol and low density lipoprotein (LDL) on the acyl-coenzyme A: cholesterol acyltransferase (ACAT) activity were investigated as well. ACAT activity in nephrosis was normal, but stimulated to varying extents in the presence of these factors. On the other hand, the acylcoenzyme A:1,2-diacylglycerol acyltransferase (ADGAT) and phosphatidate phosphorylase-activities were significantly increased in the nephrotic rats. The microsomal cholesterol (free and ester) and phospholipid concentrations were normal but the triglyceride level was significantly reduced in the experimental group. We speculate that an excess production of smaller-sized VLDL particles due to altered activities of microsomal lipid synthesizing enzymes may occur in puromycin amino nucleoside induced-nephrotic rats. |
| Acyl-coenzyme A: cholesterol acyltransferase (ACAT) Miyazaki, A. and T. Watanabe (2004), Nippon Rinsho 62 Suppl 12: 89-91. |
| Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide Puglielli, L., G. Konopka, et al. (2001), Nat Cell Biol 3(10): 905-12. Abstract: The pathogenic event common to all forms of Alzheimer's disease is the abnormal accumulation of the amyloid beta-peptide (Abeta). Here we provide strong evidence that intracellular cholesterol compartmentation modulates the generation of Abeta. Using genetic, biochemical and metabolic approaches, we found that cholesteryl-ester levels are directly correlated with Abeta production. Acyl-coenzyme A:cholesterol acyltransferase (ACAT), the enzyme that catalyses the formation of cholesteryl esters, modulates the generation of Abeta through the tight control of the equilibrium between free cholesterol and cholesteryl esters. We also show that pharmacological inhibitors of ACAT, developed for the treatment of atherosclerosis, are potent modulators of Abeta generation, indicating their potential for use in the treatment of Alzheimer's disease. |