Abstract：
:The novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor CP-113,818 has been characterized in vitro against ACAT isolated from liver and intestine from a variety of species including human subjects, and in vivo in cholesterol-fed rats, hamsters, rabbits, and two species of nonhuman primates. CP-113,818 is a potent and specific inhibitor of liver and intestinal ACAT with IC50s ranging from 17 to 75 nM. This ACAT inhibitor also prevented the absorption of exogenous radiolabeled cholesterol in hamsters (ED50 = 6 micrograms/kg), rabbits (ED50 1/2 10 micrograms/kg), and cynomolgus and African green monkeys (40 and 26% inhibition at 10 mg/kg, respectively). CP-113,818 effectively prevented the increase in liver cholesterol levels in cholesterol-fed rats, hamsters, and rabbits. In lipoprotein characterization studies in rabbits, CP-113,818 selectively decreased apoB-containing lipoproteins (beta-VLDL, IDL, and LDL) and shifted the distribution of cholesterol from beta-VLDL, IDL, and LDL (96% before treatment to 81% after treatment) to HDL (4% before treatment to 19% after treatment). Finally, in monkeys, CP-113,818 significantly decreased LDL cholesterol by approximately 30% while either increasing HDL cholesterol (cynomolgus monkeys) or not affecting HDL cholesterol (African green monkeys), thereby improving the total plasma cholesterol/HDL ratios. In summary, CP-113,818 significantly inhibited cholesterol absorption, prevented the increase in liver cholesterol, and improved the lipoprotein profiles by selectively decreasing the cholesterol concentrations of the atherogenic lipoproteins (VLDL, IDL, and LDL) in a variety of cholesterol-fed animals. These data suggest that ACAT inhibition may be a useful therapeutic approach for lowering LDL cholesterol and thereby reducing the risk of developing coronary heart disease.
journal_name
J Lipid Resjournal_title
Journal of lipid researchauthors
Marzetta CA,Savoy YE,Freeman AM,Long CA,Pettini JL,Hagar RE,Inskeep PB,Davis K,Stucchi AF,Nicolosi RJsubject
Has Abstract,Author List Incompletepub_date
1994-10-01 00:00:00pages
1829-38issue
10eissn
0022-2275issn
1539-7262journal_volume
35pub_type
杂志文章abstract：:Smith-Lemli-Opitz syndrome (SLOS) is a genetic disorder characterized by low plasma cholesterol and high 7-dehydrocholesterol (7-DHC). Synthesis of cholesterol and 7-DHC and its metabolites is regulated by HMG-CoA reductase, whose activity can be measured by 24-h excretion of its product mevalonate. We devised a simpl...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：10.1194/jlr.m200163-jlr200
更新日期：2002-10-01 00:00:00
abstract：:Sonication of rat fat cells caused an increase in lipolysis in the absence of lipolytic stimulants (basal lipolysis) and loss of epinephrine responsiveness. Sonication of endogenous lipid droplets from fat cells also induced an increase in lipolysis in the presence of hormone-sensitive lipase (HSL) and loss of epineph...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1994-01-01 00:00:00
abstract：:In a previously described method for determining the activity of cerebroside galactosidase, the enzyme preparation was incubated with an emulsion of cerebroside which had been labeled in the galactose moiety. The liberated galactose was separated from the emulsion by liquid-liquid partitioning, but the presence of det...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1971-03-01 00:00:00
abstract：:Bile acids are a group of molecular species of acidic steroids with peculiar physical-chemical and biological characteristics. At high concentrations they become toxic to mammalian cells, and their presence is pertinent in the pathogenesis of several liver diseases and colon cancer. Bile acid cytoxicity has been relat...
journal_title：Journal of lipid research
pub_type： 杂志文章,评审
doi：10.1194/jlr.R900011-JLR200
更新日期：2009-09-01 00:00:00
abstract：:It is becoming increasingly accepted that removal of cellular cholesterol occurs by at least two pathways, one involving the well-described aqueous diffusion mechanism and another promoted by lipid-free apolipoproteins. We compared the contribution of apolipoprotein-dependent and -independent pathways, taking into con...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1997-09-01 00:00:00
abstract：:The sialic acid present in erythrocyte ghosts was estimated by methane chemical ionization mass fragmentography of the trimethylsilyl methyl glycosides. The internal standard was 3,4,6-tris-trimethylsilyl-alpha-phenyl-2-deoxy-2-acetamide-D-glucosaminide, as proposed by Yu and Ledeen (J. Lipid Res. 1970. 11: 506-516). ...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1980-11-01 00:00:00
abstract：:Thioesterase superfamily member 1 (Them1; synonyms acyl-CoA thioesterase 11 and StarD14) is highly expressed in brown adipose tissue and limits energy expenditure in mice. Them1 is a putative fatty acyl-CoA thioesterase that comprises tandem hot dog-fold thioesterase domains and a lipid-binding C-terminal steroidogeni...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：10.1194/jlr.M029538
更新日期：2012-12-01 00:00:00
abstract：:Small angle X-ray diffraction was used to examine arterial smooth muscle cell (SMC) plasma membranes isolated from control and cholesterol-fed (2%) atherosclerotic rabbits. A microsomal membrane enriched with plasma membrane obtained from animals fed cholesterol for up to 13 weeks showed a progressive elevation in the...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1998-05-01 00:00:00
abstract：:Potentially atherogenic triglyceride-rich lipoprotein (TRL) remnants can be isolated and quantitated as remnant-like particles (RLP), using an immunoaffinity gel containing specific anti-human apolipoprotein A-I (apoA-I) and apoB-100 monoclonal antibodies. The aim of the present study was to determine the relationship...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：2000-09-01 00:00:00
abstract：:Adipocyte triglyceride storage provides a reservoir of energy that allows the organism to survive times of nutrient scarcity, but excessive adiposity has emerged as a health problem in many areas of the world. Monoacylglycerol acyltransferase (MGAT) acylates monoacylglycerol to produce diacylglycerol; the penultimate ...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：10.1194/jlr.M084947
更新日期：2018-09-01 00:00:00
abstract：:Nuclear hormone receptors liver X receptor (LXRalpha and LXRbeta) ligands are attractive approaches for the treatment of dyslipidemia and atherosclerosis. To further elucidate the function of LXRalpha in liver lipid metabolism in a disease-relevant animal model, the KKAy mouse, we used adenoviral vectors to selectivel...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：10.1194/jlr.M700571-JLR200
更新日期：2009-01-01 00:00:00
abstract：:Mice with a targeted mutation of 3beta-hydroxysterol Delta(7)-reductase (Dhcr7) that cannot convert 7-dehydrocholesterol to cholesterol were used to identify the origin of fetal sterols. Because their heterozygous mothers synthesize cholesterol normally, virtually all sterols found in a Dhcr7 knockout fetus having a D...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：10.1194/jlr.M600141-JLR200
更新日期：2006-07-01 00:00:00
abstract：:Arterial wall lipid retention is believed to be due primarily to ionic interactions between lipoproteins and proteoglycans. Thus, oxidized low density lipoproteins (LDL), with decreased positive charge relative to native LDL, should have decreased interaction with negatively charged proteoglycans. However, oxidized LD...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：2001-05-01 00:00:00
abstract：:A molecular model was built for human lecithin:cholesterol acyltransferase (LCAT) based upon the structural homology between this enzyme and lipases (Peelman et al. 1998. Prot. Sci. 7: 585-597). We proposed that LCAT belongs to the alpha/beta hydrolase fold family, and that the central domain of LCAT consists of a mix...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1999-01-01 00:00:00
abstract：:At onset of egg-laying in the chicken, plasma levels of apolipoprotein VLDL-II (apoII) increase dramatically, suggesting a function of apoII in yolk deposition of triglyceride-rich lipoproteins. Thus, the possibility that this female-specific homodimeric protein (Mr of subunit, 9500) is recognized by the oocyte recept...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1988-05-01 00:00:00
abstract：:In addition to functioning as detergents that aid digestion of dietary lipids in the intestine, some bile acids have been shown to exhibit antimicrobial activity. However, detailed information on the bactericidal activities of the diverse molecular species of bile acid in humans and rodents is largely unknown. Here, w...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：10.1194/jlr.M075143
更新日期：2017-06-01 00:00:00
abstract：:The phase behavior and temperature-dependent molecular motions of three cholesteryl ethers (caproyl, myristyl, oleyl) and a cholesteryl carbonate (oleyl) were characterized. The properties of each ether were qualitatively similar to, but quantitatively different from, those of the corresponding cholesteryl ester. For ...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1987-12-01 00:00:00
abstract：:Fatty liver is frequent in the apolipoprotein B (apoB)-defective genetic form of familial hypobetalipoproteinemia (FHBL), but interindividual variability in liver fat is large. To explain this, we assessed the roles of metabolic factors in 32 affected family members with apoB-defective FHBL and 33 related and unrelate...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：10.1194/jlr.M300508-JLR200
更新日期：2004-05-01 00:00:00
abstract：:The action of cycloheximide on some parameters of glucose and lipid metabolism was studied in vitro in epidiymal fat pads from fasted rats. Incubation of fat pads with cycloheximide (1 mug/ml) for 2 hours resulted in a two-fold increase in glucose uptake, glucose oxidation, incorporation of glucose into lipids, and re...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1977-01-01 00:00:00
abstract：:To study the mechanisms of hepatic HDL formation, we investigated the roles of ABCA1, ABCG1, and SR-BI in nascent HDL formation in primary hepatocytes isolated from mice deficient in ABCA1, ABCG1, or SR-BI and from wild-type (WT) mice. Under basal conditions, in WT hepatocytes, cholesterol efflux to exogenous apoA-I w...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：10.1194/jlr.M017079
更新日期：2012-03-01 00:00:00
abstract：:In mammals, white adipose tissue (WAT) stores and releases lipids, whereas brown adipose tissue (BAT) oxidizes lipids to fuel thermogenesis. In obese individuals, WAT undergoes profound changes; it expands, becomes dysfunctional, and develops a low-grade inflammatory state. Importantly, BAT content and activity declin...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：10.1194/jlr.M079665
更新日期：2018-05-01 00:00:00
abstract：:The alpha-naphthylisothiocyanate (ANIT)-treated rat was evaluated as a model for lipoprotein metabolism in cholestatic liver disease. Alterations in lipoprotein composition over a period of 120 h after ANIT treatment (100 mg/kg) were studied. Eighteen hours after treatment, plasma bilirubin and bile acid levels began ...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1996-05-01 00:00:00
abstract：:Bacterial lipopolysaccharides (LPSs or endotoxins) can bind most proteins of the lipid transfer/LPS-binding protein (LT/LBP) family in host organisms. The LPS-bound LT/LBP proteins then trigger either an LPS-induced proinflammatory cascade or LPS binding to lipoproteins that are involved in endotoxin inactivation and ...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：10.1194/jlr.RA120000704
更新日期：2020-12-15 00:00:00
abstract：:Dihydroxyacetone phosphate acyl transferase (DHAP-AT), alkyl dihydroxyacetone phosphate synthase (alkyl-DHAP-synthase), and glycerol-3-phosphate acyltransferase (GPAT) activities were investigated under optimal assay conditions using highly purified organelle preparations. The data presented clearly indicate that GPAT...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1993-03-01 00:00:00
abstract：:The proton NMR spectra of the N-methyl choline region of normal and lecithin:cholesterol acyltransferase (LCAT)-deficient lipoproteins and of egg yolk phosphatidylcholine-cholesterol 55:45 (mol %) vesicle mixtures have been examined in the presence and absence of manganous sulfate as a line-broadening reagent. Mangano...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1989-05-01 00:00:00
abstract：:In order to study the metabolic responses of humans consuming a diet moderately high in cholesterol content, we carried out a long-term sterol balance study, up to 25 weeks in duration. Two subjects, one normocholesterolemic and one hypercholesterolemic, were given, in sequence, a very low cholesterol diet and then a ...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1980-11-01 00:00:00
abstract：:Vitamin A-transporting protein in chicken plasma was purified by column chromatography on DEAE-Sephadex and Sephadex G-100; the protein formed a complex of retinol-binding protein (RBP) with prealbumin (PA). The molecular weight of the 1:1 molar complex was estimated to be 76,000 by gel filtration, and the sedimentati...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1975-05-01 00:00:00
abstract：:Liver cells isolated from normal and cholestyramine-treated rats were incubated as cell suspensions for up to 4 hr in a simple, defined medium. The bile acid concentration in cells plus cell medium was determined by gas-liquid chromatography. Normal hepatocytes synthesized cholic acid at an initial rate of 0.25 nmol/m...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1979-09-01 00:00:00
abstract：:PPARs regulate the expression of genes for energy metabolism in a ligand-dependent manner. PPARs can influence fatty acid oxidation, the level of circulating triglycerides, glucose uptake and insulin sensitivity. Here, we demonstrate that 5-hydroxyeicosapentaenoic acid (HEPE), 8-HEPE, 9-HEPE, 12-HEPE and 18-HEPE (hydr...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：10.1194/jlr.M047514
更新日期：2014-05-01 00:00:00
abstract：:These studies examined the proposition that the small particle size of HDL3 in the plasma of hypertriglyceridemic subjects is the consequence of the sequential actions of lipid transfer protein and hepatic lipase on HDL. Incubation of unmodified total HDL or HDL3 in the presence of hepatic lipase resulted in a depleti...
journal_title：Journal of lipid research
pub_type： 杂志文章
doi：
更新日期：1986-12-01 00:00:00
