Ca++ antagonists and ACAT inhibitors promote cholesterol efflux from macrophages by different mechanisms. I. Characterization of cellular lipid metabolism.

Schmitz, Gerd; Robenek, Horst; Beuck, Martin; Krause, Renee J.; Schurek, A; Niemann, Reinhard

doi:10.1161/01.atv.8.1.46

Cited by 119 publications

(36 citation statements)

References 54 publications

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“…However, further detailed studies are necessary to clarify its mechanism. Recently, several investigators reported that ACAT inhibition inhibited foam cell formation (28) and prevented release into the circulation of apo B and VLDL-cholesterol at the liver both in vitro (7) and in vivo (8,9). Thus, besides dietary hypercholesterolemia, F-1394 may also have therapeutic potentials for the treatment of atherosclerosis as well as non-dietary hypercholesterolemia.…”

Section: Discussionmentioning

confidence: 99%

Hypocholesterolemic Action and Prevention of Cholesterol Absorption via the Gut by F-1394, a Potent Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitor, in Cholesterol Diet-Fed Rats

Kusunoki

Aragane

Kitamine

et al. 1995

Japanese Journal of Pharmacology

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ABSTRACT-In the present study, we investigated the hypocholesterolemic effect of F-1394 ((ls,2s)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]aminocyclohexane-1-yl 3-[N-(2,2, 5, 5-tetramethyl-1, 3-dioxane-4-carbonyl)amino]propionate), a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), and the effect on cholesterol absorption via the gut in rats fed a 1 % cholesterol diet. Single administration of F-1394 to the cholesterol diet-fed rats at the doses of 3-30 mg/kg, p.o. decreased the serum cholesterol levels by 16 -54% 3 hr after the administration. The ACAT activity in the small intestinal mucosa of the rats given orally F-1394 (30 mg/kg) was significantly inhibited 3 hr after the administration. The hypocholesterolemic action of F-1394 had a faster onset than that of DL-melinamide or CL-277,082. The study by the dual isotope ratio method showed that F-1394 (30 mg/kg, p.o.) significantly suppressed the dietary cholesterol absorption. Furthermore, in the determination of cholesterol absorption by using 14C-cholesterol as the oral tracer, the administration of F-1394 (30 mg/kg, p.o.) 1 or 2 hr before or immediately after the application of the oral tracer significantly prevented the appearance of the radioactivity in the circulation by around 90%. These results indicate that oral administration of F-1394 inhibits the ACAT activity in the small intestinal mucosa and subsequently contributes much to the prevention of cholesterol absorption via the gut, resulting in the decrease in serum cholesterol levels in the cholesterol diet-fed rats. Furthermore, the effect of F-1394 appears immediately after its administration in contrast to that of DL-melinamide or CL-277,082.

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Section: Discussionmentioning

confidence: 99%

Hypocholesterolemic Action and Prevention of Cholesterol Absorption via the Gut by F-1394, a Potent Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitor, in Cholesterol Diet-Fed Rats

Kusunoki

Aragane

Kitamine

et al. 1995

Japanese Journal of Pharmacology

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“…In adrenal cortex and ovary, ACAT' and neutral cholesteryl ester hydrolase regulate the intracellular storage pool of cholesterol for synthesis of steroidogenic hormones (31,(38)(39)(40)(41). ACAT activity has also been identified in placenta (33), lactating mammary gland (32), lung (19), aorta (5), macrophages (7,27,29,30), arterial smooth muscle cells (28,36), and fibroblasts of the lung (35) and skin (6,36). The physiologic role of ACAT in some of these tissues and cell types has not been clearly delineated. Cholesteryl esters can be a major form of tissue cholesterol in normal physiologic processes as well as pathologic conditions.…”

Section: Introductionmentioning

confidence: 99%

Toxicologic Effects of a Novel Acyl-CoA: Cholesterol Acyltransferase Inhibitor in Cynomolgus Monkeys

Reindel¹,

Dominick²,

Bocan³

et al. 1994

Toxicol Pathol

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“…Lastly, in studies of mouse peritoneal macrophages, investigators have shown that the ACAT inhibitor octimibate, when present during foam cell formation, actually increased the uptake and degradation of acLDL and the accumulation of cholesterol in these cells. 8 ACAT inhibitors have also been studied in cultured primary human monocyte-derived macrophages (HMMs). HMMs can become lipid enriched when incubated with modified LDL 9 and have also been shown to release UC in the absence of added cholesterol acceptors in the medium.…”

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confidence: 99%

Novel Effects of the Acyl-Coenzyme A:Cholesterol Acyltransferase Inhibitor 58-035 on Foam Cell Development in Primary Human Monocyte–Derived Macrophages

Rodríguez¹,

Bachorik

Wee³

1999

ATVB

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Abstract-We examined the effect of acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors on intracellular cholesterol stores in primary human monocyte-derived macrophages (HMMs) during foam cell formation. HMMs were exposed to acetylated low density lipoprotein (acLDL, 500 g protein per mL) with or without 58-035 (1 to 10 g/mL) or CI-976 (2 g/mL) for 2 to 48 hours. Total cholesterol (TC) and esterified cholesterol (EC) mass was significantly lower while unesterified cholesterol (UC) increased slightly in cells incubated with acLDL plus ACAT inhibitors. Sterol mass was also measured in cells coincubated with acLDL (500 g protein per mL) with or without 58-035 (2 g/mL), high density lipoprotein (HDL, 400 g protein per mL), or HDLϩ58-035 for 48 hours. TC and EC were 23% and 55% lower, respectively (PϽ0.0004), while UC was 11% higher (PϽ0.04) in cells incubated with acLDL plus 58-035. In contrast, coincubation with HDL alone did not significantly affect TC, EC, or UC mass compared with acLDL alone. The effect of 58-035 could not be explained by cytotoxicity, because adenine release, secreted lactate dehydrogenase, glucose utilization, and cell protein were similar in cells exposed to acLDL regardless of the presence of 58-035. We investigated several potential mechanisms for the decreased TC mass, including increased UC efflux and decreased acLDL binding and uptake. Efflux was measured in cells exposed to [1,2-3 H]cholesteryl oleate-labeled acLDL, unlabeled control acLDL, and native untreated acLDL (500 g protein per mL) with or without 58-035 (5 g/mL) for 24 or 48 hours. UC efflux increased in a time-dependent manner from cells exposed to acLDL plus 58-035 compared with cells exposed to acLDL alone (PϽ0.04). High-affinity binding was measured in cells exposed to 125 I-acLDL (5 g protein per mL) with or without excess unlabeled acLDL (100 or 500 g protein per mL) for 4 hours at 4°C. Specific acLDL binding, uptake, and total degradation were significantly lower when 58-035 was present during cholesterol enrichment compared with cells exposed to acLDL alone (PϽ0.001). Unlike the effects of ACAT inhibitors on foam cell formation in rodent macrophages, these compounds lowered TC accumulation in HMMs during foam cell formation by limiting the uptake of acLDL and enhancing UC efflux. They may offer promise as drug therapies for atherosclerosis.

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Ca++ antagonists and ACAT inhibitors promote cholesterol efflux from macrophages by different mechanisms. I. Characterization of cellular lipid metabolism.

Abstract: The effects of the slow C a + + channel blocker, nlfedlplne, and ACAT Inhibitor, octlmlbate, on the cholesterol metabolism of cholesterol-loaded macrophages were compared. We demonstrated that apollpoproteln A-) containing high density llpoprotelns (

Cited by 119 publications

References 54 publications

Hypocholesterolemic Action and Prevention of Cholesterol Absorption via the Gut by F-1394, a Potent Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitor, in Cholesterol Diet-Fed Rats

Hypocholesterolemic Action and Prevention of Cholesterol Absorption via the Gut by F-1394, a Potent Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitor, in Cholesterol Diet-Fed Rats

Toxicologic Effects of a Novel Acyl-CoA: Cholesterol Acyltransferase Inhibitor in Cynomolgus Monkeys

Novel Effects of the Acyl-Coenzyme A:Cholesterol Acyltransferase Inhibitor 58-035 on Foam Cell Development in Primary Human Monocyte–Derived Macrophages

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