Inhibitors of Acyl-CoA:Cholesterol <i>O</i>-Acyl Transferase (ACAT) as Hypocholesterolemic Agents. CI-1011:  An Acyl Sulfamate with Unique Cholesterol-Lowering Activity in Animals Fed Noncholesterol-Supplemented Diets

Lee, Helen T.; Sliskovic, Drago R.; Picard, J. A.; Roth, Bruce D.; Wierenga, Wendell; Hicks, James L.; Bousley, Richard F.; Hamelehle, Katherine L.; Homan, Reynold; Speyer, Cecilia L.; Stanfield, R. L.; Krause, Brian R.

doi:10.1021/jm960674d

Cited by 88 publications

(63 citation statements)

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“…The structures of these 2 inhibitors are different. 28,62 DuP 128 is a lipophilic, noncompetitive ACAT inhibitor with limited oral bioavailability 23 and an in vitro IC 50 of 10 nmol/L for rat liver microsomal ACAT activity. 63,64 In contrast, CI-1011, is an acyl sulfamate with quite different physiochemical properties compared with the more lipophilic, typical ACAT inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…63,64 In contrast, CI-1011, is an acyl sulfamate with quite different physiochemical properties compared with the more lipophilic, typical ACAT inhibitors. 28 CI-1011 has a high IC 50 , ranging from 12 mol/L to 60 nmol/L depending on ACAT assay conditions. 28 How these structural differences result in the differential effects on the regulation of apoB secretion are currently unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in chow-fed rats and rabbits fed a cholesterol-free casein diet revealed that CI-1011 is more effective in reducing plasma total cholesterol (TC) levels than equivalent doses of DuP 128. 28 Previous in vivo apoB kinetic studies from this laboratory have shown that DuP 128, a potent noncompetitive inhibitor of ACAT, significantly inhibited hepatic ACAT when administered to pigs intravenously. 23,29 This was associated with a significant decrease in the VLDL apoB secretion into plasma, but had no effect on LDL apoB production.…”

mentioning

confidence: 96%

“…A recently developed ACAT inhibitor, CI-1011, has marked lipid and apoB lowering ability in vivo, 30 -32 and displays ACAT inhibitory activity in vitro. 28 In contrast to DuP 128, oral administration of CI-1011 decreased both VLDL and LDL apoB production rates in apoB kinetic studies performed in pigs. 33 These 2 inhibitors differ in structure, lipid solubility, and 50% inhibitory concentration (IC 50 ), raising the possibility that the mechanism(s) by which these inhibitors regulate apoB secretion may differ.…”

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confidence: 97%

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ApoB100 Secretion From HepG2 Cells is Decreased by the ACAT Inhibitor CI-1011

Wilcox

Barrett

Newton

et al. 1999

ATVB

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Abstract-The concept that hepatic cholesteryl ester (CE) mass and the rate of cholesterol esterification regulate hepatocyte assembly and secretion of apoB-containing lipoproteins remains controversial. The present study was carried out in HepG2 cells to correlate the rate of cholesterol esterification and CE mass with apoB secretion by CI-1011, an acyl CoA:cholesterol acyltransferase (ACAT) inhibitor that is known to decrease apoB secretion, in vivo, in miniature pigs. HepG2 cells were incubated with CI-1011 (10 nmol/L, 1 mol/L, and 10 mol/L) for 24 hours. ApoB secretion into media was decreased by 25%, 27%, and 43%, respectively (PϽ0.0012). CI-1011 (10 mol/L) inhibited HepG2 cell ACAT activity by 79% (PϽ0.002) and cellular CE mass by 32% (PϽ0.05). In contrast, another ACAT inhibitor, DuP 128 (10 mol/L), decreased cellular ACAT activity and CE mass by 85% (PϽ0.002) and 42% (Pϭ0.01), respectively, but had no effect on apoB secretion into media. To characterize the reduction in apoB secretion by CI-1011, pulse-chase experiments were performed and analyzed by multicompartmental modelling using SAAM II. CI-1011 did not affect the synthesis of apoB or albumin. However, apoB secretion into the media was decreased by 42% (Pϭ0.019). Intracellular apoB degradation increased proportionately (Pϭ0.019). A poB100, synthesized in the liver, is an essential structural component of VLDL and its metabolic products, IDL and LDL. 1,2 ApoB is required for the intracellular assembly and secretion of these lipoproteins, and serves as a ligand for LDL receptor-mediated clearance of these particles from the plasma. 3 Hepatic overproduction of apoB-containing lipoproteins is a major risk factor for atherosclerosis. Therefore, studies designed to understand the processes regulating apoB assembly and secretion from hepatocytes are important. The production of these lipoproteins is complex and requires the coordinated synthesis and assembly of apoB, triglyceride (TG), free and esterified cholesterol (FC; cholesteryl ester, CE), phospholipids (PLs), and other components. Although considerable progress has been made in understanding these processes, many questions remain unresolved.ApoB is thought to be regulated primarily at posttranscriptional levels. The rates of apoB translocation across the endoplasmic reticulum (ER) membrane and intracellular degradation are believed to regulate the amount of apoBcontaining lipoproteins secreted from the liver. 4,5 Therefore, the secretion rate of apoB results from the proportion of newly synthesized apoB molecules that associate with lipid and move through the secretory pathway, versus the proportion that are degraded within the cell shortly after, or during, their synthesis. Although hepatic regulation of apoB secretion is generally considered to occur posttranslationally, transcriptional regulation may also play a minor role. Increased delivery of 25-hydroxycholesterol 6 or VLDL 7 to cultured hepatocytes has been shown to affect mRNA levels and secretion efficiency of apoB.Several factors have been...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 96%

mentioning

confidence: 97%

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ApoB100 Secretion From HepG2 Cells is Decreased by the ACAT Inhibitor CI-1011

Wilcox

Barrett

Newton

et al. 1999

ATVB

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“…The amount given represents the midrange of the effective dose (10 to 50 mg · kg Ϫ1 · d Ϫ1 ) in experimental animals. 42 The untreated nephrotic and control groups were fed drug-free food. The animals were housed in a temperature-controlled facility with 12-hour light/dark cycles.…”

Section: Animalsmentioning

confidence: 99%

Acyl-Coenzyme A:Cholesterol Acyltransferase Inhibition Ameliorates Proteinuria, Hyperlipidemia, Lecithin-Cholesterol Acyltransferase, SRB-1, and Low-Denisty Lipoprotein Receptor Deficiencies in Nephrotic Syndrome

Vaziri

Liang

2004

Circulation

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Background-Nephrotic syndrome (NS) is associated with hyperlipidemia, altered lipid regulatory enzymes and receptors, and increased risk of progressive renal and cardiovascular diseases. Acyl-coenzyme A:cholesterol acyltransferase (ACAT) catalyzes intracellular esterification of cholesterol and plays an important role in production of apolipoprotein B-containing lipoproteins, regulation of cholesterol-responsive proteins, and formation of foam cells. Because hepatic ACAT-2 is markedly upregulated in NS, we tested the hypothesis that inhibition of ACAT may improve cholesterol metabolism in NS. Methods and Results-Rats with puromycin-induced NS were treated with either the ACAT inhibitor CI-976 or placebo for 2 weeks. Normal rats served as controls. Plasma lipids, renal function, and key lipid regulatory factors were measured. Untreated NS rats showed heavy proteinuria; hypoalbuminemia; elevated plasma cholesterol, triglyceride, LDL, VLDL, and total cholesterol-to-HDL cholesterol ratio; increased hepatic ACAT activity, ACAT-2 mRNA, and ACAT-2 protein; and reduced LDL receptor, HDL receptor, otherwise known as scavenger receptor B-1 (SRB-1) and plasma lecithin-cholesterol acyltransferase (LCAT). ACAT inhibitor reduced plasma cholesterol and triglycerides, normalized total cholesterol-to-HDL cholesterol ratio, and lowered hepatic ACAT activity without changing ACAT-2 mRNA or protein. This was accompanied by near normalizations of plasma LCAT, hepatic SRB-1, and LDL receptor and a significant amelioration of proteinuria and hypoalbuminemia. Conclusions-Pharmacological

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Acyl‐CoenzymeA:Cholesterol Acyltransferase

Chang

2002

Wiley Encyclopedia of Molecular Medicine

105

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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.

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Inhibitors of Acyl-CoA:Cholesterol O-Acyl Transferase (ACAT) as Hypocholesterolemic Agents. CI-1011: An Acyl Sulfamate with Unique Cholesterol-Lowering Activity in Animals Fed Noncholesterol-Supplemented Diets

Cited by 88 publications

References 14 publications

ApoB100 Secretion From HepG2 Cells is Decreased by the ACAT Inhibitor CI-1011

ApoB100 Secretion From HepG2 Cells is Decreased by the ACAT Inhibitor CI-1011

Acyl-Coenzyme A:Cholesterol Acyltransferase Inhibition Ameliorates Proteinuria, Hyperlipidemia, Lecithin-Cholesterol Acyltransferase, SRB-1, and Low-Denisty Lipoprotein Receptor Deficiencies in Nephrotic Syndrome

Acyl‐CoenzymeA:Cholesterol Acyltransferase

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