Immunodepletion experiments suggest that acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) protein plays a major catalytic role in adult human liver, adrenal gland, macrophages, and kidney, but not in intestines

Lee, Oneil; Chang, Catherine C.Y.; Lee, William; Chang, Ta−Yuan

doi:10.1016/s0022-2275(20)32203-3

Cited by 91 publications

(16 citation statements)

References 23 publications

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“…HepG2 cells (54). Interestingly, although ACAT1 does not appear to play a major catalytic role in mouse liver (54), immunodepletion experiments using primary human hepatocytes suggest that it does play a role adult human liver (57).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ACAT by avasimibe decreases both VLDL and LDL apolipoprotein B production in miniature pigs

Burnett

Wilcox

Telford

et al. 1999

Journal of Lipid Research

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An orally bioavailable acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor, avasimibe (CI-1011), was used to test the hypothesis that inhibition of cholesterol esterification, in vivo, would reduce hepatic very low density (VLDL) apolipoprotein (apo) B secretion into plasma. ApoB kinetic studies were carried out in 10 control miniature pigs, and in 10 animals treated with avasimibe (10 mg/kg/d, n ‫؍‬ 6; 25 mg/kg/d, n ‫؍‬ 4). Pigs were fed a diet containing fat (34% of calories) and cholesterol (400 mg/d; 0.1%). Avasimibe decreased the plasma concentrations of total triglyceride, VLDL triglyceride, and VLDL cholesterol by 31-40% 39-48%, and 31-35%, respectively. Significant reductions in plasma total cholesterol (35%) and low density lipoprotein (LDL) cholesterol (51%) concentrations were observed only with high dose avasimibe. Autologous 131 I-labeled VLDL, 125 Ilabeled LDL, and [ 3 H]leucine were injected simultaneously into each pig and apoB kinetic data were analyzed using multicompartmental analysis (SAAM II). Avasimibe decreased the VLDL apoB pool size by 40-43% and the hepatic secretion rate of VLDL apoB by 38-41%, but did not alter its fractional catabolism. Avasimibe decreased the LDL apoB pool size by 13-57%, largely due to a dose-dependent 25-63% in the LDL apoB production rate. Hepatic LDL receptor mRNA abundances were unchanged, consistent with a marginal decrease in LDL apoB FCRs. Hepatic ACAT activity was decreased by 51% ( P ‫؍‬ 0.050) and 68% ( P ‫؍‬ 0.087) by low and high dose avasimibe, respectively. The decrease in total apoB secretion correlated with the decrease in hepatic ACAT activity ( r ‫؍‬ 0.495; P ‫؍‬ 0.026). We conclude that inhibition of hepatic ACAT by avasimibe reduces both plasma VLDL and LDL apoB concentrations, primarily by decreasing apoB secretion. -Burnett,

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Section: Discussionmentioning

confidence: 99%

Inhibition of ACAT by avasimibe decreases both VLDL and LDL apolipoprotein B production in miniature pigs

Burnett

Wilcox

Telford

et al. 1999

Journal of Lipid Research

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“…Furthermore, ACAT1 and ACAT2 responded in a different manner to ACAT inhibitors of differing structures and classes [12]. Interestingly, although ACAT1 does not appear to play a major catalytic role in mouse liver [12], immunodepletion experiments using primary human hepatocytes suggest that it does in adult human liver [14].…”

Section: Multiple Acat Genesmentioning

confidence: 97%

Acyl‐CoenzymeA:Cholesterol Acyltransferase

Chang

2002

Wiley Encyclopedia of Molecular Medicine

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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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“…Acyl-coenzyme A (CoA):cholesterol O -acyltransferase (ACAT), also known as sterol O -acyltransferase (SOAT), catalyzes the acylation of free cholesterol with long-chain fatty acids to form cholesteryl esters (CEs) . Two ACATs have been identified: ACAT-1 and ACAT-2. − ACAT-1 is the main isoenzyme in the brain, and in multiple neurodegenerative diseases including Alzheimer’s disease (AD), inhibition of ACAT-1 provides several benefits, such as the clearance of amyloid beta (Αβ) peptides and suppression of 24( S )-hydroxycholesterol (24S-OHC)-induced neuronal cell death. − Recent studies also reported that blocking cholesterol esterification via ACAT-1 inhibition is a promising therapeutic strategy to treat glioblastoma (GBM). , This evidence has shed light on the previous use of ACAT inhibitors for the treatment of brain disease. However, ACAT inhibitors have poor blood–brain barrier (BBB) permeability because they were developed with the goal of treating peripheral arterial disease.…”

Section: Introductionmentioning

confidence: 99%

Brain Targeting of Acyl-CoA:Cholesterol O-Acyltransferase-1 Inhibitor K-604 via the Intranasal Route Using a Hydroxycarboxylic Acid Solution

Shibuya¹,

Morikawa²,

Miyamoto³

et al. 2019

ACS Omega

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An acyl-CoA:cholesterol O-acyltransferase-1 (ACAT-1/SOAT-1) inhibitor, K-604 is a promising drug candidate for the treatment of Alzheimer’s disease and glioblastoma; however, it exhibits poor solubility in neutral water and low permeability across the blood–brain barrier. In this study, we report the successful delivery of K-604 to the brain via the intranasal route in mice using a hydroxycarboxylic acid solution. In cerebral tissue, the AUC of K-604 after intranasal administration (10 μL; 108 μg of K-604/mouse) was 772 ng·min/g, whereas that after oral administration (166 μg of K-604/mouse) was 8.9 ng·min/g. Thus, the index of brain-targeting efficiency was 133-fold based on the dose conversion. Even with intranasal administration of K-604 once per day for 7 days, the level of cholesteryl esters markedly decreased from 0.70 to 0.04 μmol/g in the mouse brain. Thus, this application will be a crucial therapeutic solution for ACAT-1 overexpressing diseases in the brain.

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Immunodepletion experiments suggest that acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) protein plays a major catalytic role in adult human liver, adrenal gland, macrophages, and kidney, but not in intestines

Cited by 91 publications

References 23 publications

Inhibition of ACAT by avasimibe decreases both VLDL and LDL apolipoprotein B production in miniature pigs

Inhibition of ACAT by avasimibe decreases both VLDL and LDL apolipoprotein B production in miniature pigs

Acyl‐CoenzymeA:Cholesterol Acyltransferase

Brain Targeting of Acyl-CoA:Cholesterol O-Acyltransferase-1 Inhibitor K-604 via the Intranasal Route Using a Hydroxycarboxylic Acid Solution

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