Disease relevance of Soat1

• Severe hypercholesterolemia in the NS group was coupled with depressed liver tissue free cholesterol concentration and marked increases in hepatic ACAT mRNA, protein and enzymatic activity [1].
• Up-regulation of acyl-coenzyme A:cholesterol acyltransferase (ACAT) in nephrotic syndrome [1].
• CONCLUSIONS: NS results in marked up-regulation of hepatic ACAT, which is primarily due to proteinuria and not hypoalbuminemia, since the latter alone, as seen in NAG rats, does not significantly impact ACAT expression [1].
• Upregulation of acyl-CoA: cholesterol acyltransferase in chronic renal failure [2].
• ACAT plays a major role in hepatic production and release of VLDL, intestinal absorption of cholesterol, foam cell formation, and atherogenesis [2].

Psychiatry related information on Soat1

• The influence of progesterone levels and changes in feeding patterns during gestation were considered as factors in these variations in ACAT activity [3].

High impact information on Soat1

• By 2 h, ACAT activity and biliary cholesterol secretion were at control levels [4].
• Administration of 25-hydroxycholesterol decreased HMG CoA reductase activity, increased ACAT activity, and decreased biliary cholesterol output 26% by 1 h [4].
• Administration of mevinolin, a competitive inhibitor of HMG CoA reductase, had no effect on ACAT activity and decreased biliary cholesterol secretion 16% [4].
• Parabiont rats were used to study the regulation of intestinal cholesterol synthesis (3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase activity) and esterification (acylcoenzyme A/cholesterol acyltransferase [ACAT] activity) by lipoproteins and micellar cholesterol [5].
• Regulation of acylcoenzyme A. Cholesterol acyltransferase and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity by lipoproteins in the intestine of parabiont rats [5].

Chemical compound and disease context of Soat1

• The induction of intestinal ACAT activity in diabetic rats, its modulation by insulin, and the hypocholesterolemic effects of insulin or CL-277082 treatment clearly indicate that ACAT activity plays a major role in the initiation of diabetes-associated hypercholesterolemia [6].
• Investigations utilizing the macrophage assay as an indicator for adrenal toxicity led to the identification of compounds 1g (FR190809) and 1k (FR186485, or FR195249 as its hydrochloride salt) as potent, nonadrenotoxic, orally efficacious ACAT inhibitors irrespective of the administration method [7].
• Acaterin, a novel inhibitor of acyl-CoA: cholesterol acyltransferase produced by Pseudomonas sp. A92 [8].
• To confirm this hypothesis, effects of a potent ACAT inhibitor, FR145237, on diet-induced hypercholesterolemia were examined in streptozotocin (STZ)-induced diabetic rats [9].
• Thyroxine treatment reversed these effects of hypothyroidism on ACAT activity in both organs [10].

Biological context of Soat1

• Therefore, we hypothesized that NS may result in up-regulation of hepatic ACAT [1].
• ACAT is an intracellular enzyme that catalyzes esterification of free cholesterol to cholesterol ester for storage or secretion [2].
• In the present study, we cloned rat ACAT cDNA and determined its tissue distribution [11].
• Assessment of the activity of intracellular key enzymes for cholesterol homeostasis in these rats disclosed a reduction in 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (66%, P <.005) and cholesterol 7alpha-hydroxylase (58%, P <.0004) with an increment of acyl-CoA: cholesterol acyltransferase (62%, P <.002) [12].
• The resulting HSL overexpression increased hydrolysis of cellular CEs 2- to 3-fold in lipid-laden cells in the presence of an acyl coenzyme A:cholesterol acyltransferase (ACAT) inhibitor [13].

Anatomical context of Soat1

• Expression of rat ACAT cDNA in A293 cells and CHO cells resulted in a 3.0 to 3.5-fold increase in the enzyme activity [11].
• This supports previous data that suggest that dietary or luminal cholesterol affects both HMG-CoA reductase and ACAT activity in the small intestine [5].
• The acyl-CoA: cholesterol acyltransferase reaction was 30% inhibited in hepatic microsomes of progesterone-injected rats, (p less than 0.05) [14].
• Avasimibe dose-dependently decreased ACAT activity in rat hepatocytes in the presence and absence of beta-migrating very low-density lipoproteins (betaVLDL) (by 93% and 75% at 10 micromol/L) and reduced intracellular storage of cholesteryl esters [15].
• The reaction studied in the present investigation was the conversion of cholesterol to cholesterol ester (acyl-CoA cholesterol acyltransferase) by rat liver microsomes [16].

Associations of Soat1 with chemical compounds

• Elevated ACAT in NS can contribute to dysregulation of cholesterol biosynthesis and catabolism by limiting the normal cholesterol signaling involved in regulation of these processes [1].
• ACBP and cholesterol differentially alter fatty acyl CoA utilization by microsomal ACAT [17].
• METHODS: Hepatic tissue ACAT mRNA (Northern blot), protein (Western blot) and enzymatic activity were determined in rats with puromycin-induced NS, placebo-treated control rats and Nagase hypoalbuminemic (NAG) rats [1].
• Rat ACAT cDNA, having a coding region of 1635 bp with its deduced protein sequence of 545 amino acids and two typical motifs such as signature sequences and leucine heptad motif, showed 83, 92 and 90% identity with human, mouse, and hamster ACAT, respectively [11].
• The data suggest that intestinal HMG-CoA reductase and ACAT activities are regulated by plasma lipoproteins independently of luminal factors [5].

Other interactions of Soat1

• Expression of HMG-CoA reductase is inhibited and Ch-7alpha is augmented by intracellular free cholesterol, which is avidly esterified by acyl-CoA:cholesterol acyltransferase (ACAT) [1].
• Specific activities of diacylglycerol acyltransferase, acyl-coenzyme A:cholesterol acyltransferase, and phosphatidylserine synthase (base exchange enzyme) are enriched 2.2-3.4-fold in the MAM compared with endoplasmic reticulum [18].
• To assess the role of each enzyme, [4-14C]cholesterol absorption into mesenteric lymph of rats with normal mucosal levels of both esterification enzymes was compared with that of rats with normal acyl coenzyme A:cholesterol acyltransferase activity but deficient cholesterol esterase activity [19].
• Once lactation began, reductase, cholesterol acyltransferase, 7alpha-hydroxylase activities, low density lipoprotein receptors, and mdr2 increased while SR-B1 decreased [20].
• In contrast, lysosomal acid cholesteryl esterase did not change with age, and acyl CoA: Cholesterol acyltransferase showed only a 33% decrease at 12 months of age [21].

Analytical, diagnostic and therapeutic context of Soat1

• We examined hepatic expression of ACAT-1 and ACAT-2 mRNA (Northern blot) and protein (Western blot) abundance and total ACAT activity in male CRF rats (6 wk after 5/6 nephrectomy) and sham-operated controls [2].
• Molecular cloning, functional expression and tissue distribution of rat acyl-coenzyme A:cholesterol acyltransferase [11].
• The finding that lecithin: cholesterol acyltransferase (LCAT) activity was significantly decreased in C57BL/6 mice, but not in BALB/ c mice fed the atherogenic diet, further supports this conclusion [22].
• We have recently discovered a series of imidazoles which are potent in vitro ACAT inhibitors in the J774 macrophage cell culture assay [23].
• A series of diaryl-substituted heterocyclic ureas was prepared, and their ability to inhibit acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in cholesterol-fed animal models in vivo was examined [24].

References