Disease relevance of Soat1

• Bone marrow transplantation experiments demonstrated that ACAT1 deficiency in macrophages was sufficient to cause dermal xanthomas in hyperlipidemic LDLR-deficient mice [1].
• They also exhibit a block in RBC maturation and abnormally high plasma unesterified-to-total cholesterol ratio (0.8) with associated abnormal lipoprotein morphology (lamellar/vesicular and stacked discoidal particles reminiscent of those in lecithin/cholesterol acyltransferase deficiency and cholestasis) [2].
• To further investigate the regulation of ACAT activity under controlled conditions, ACAT-deficient Chinese hamster ovary cells were stably transfected with the mouse ACAT cDNA clone driven by a cytomegalovirus promoter [3].
• Transgenic (Tg) mice that overexpress human apoA-II present functional lecithin: cholesterol acyltransferase deficiency, HDL deficiency, hypertriglyceridemia and, when fed an atherogenic diet, increased non-HDL cholesterol and increased susceptibility to atherosclerosis [4].
• We have studied the effect of macrophage ACAT1 deletion on atherogenesis in apoE-deficient (apoE-/-) mice with or without the restoration of macrophage apoE [5].

Psychiatry related information on Soat1

• Our results indicate that dietary modification of the microsomal fatty acid composition is associated with alterations in the activity of ACAT, an enzyme that is tightly bound to the microsomes [6].

High impact information on Soat1

• The importance of cholesterol ester synthesis by acyl CoA:cholesterol acyltransferase (ACAT) enzymes in intestinal and hepatic cholesterol metabolism has been unclear [7].
• Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages [8].
• The inhibition of macrophage acyl coenzyme A:cholesterol acyltransferase (ACAT), which catalyzes the formation of cholesterol esters, has been proposed as a strategy to reduce foam cell formation and to treat atherosclerosis [8].
• Although the latter findings may be associated with increased lesion stability, the marked alterations in cholesterol homeostasis indicate that selectively inhibiting ACAT1 in the setting of severe hyperlipidemia may have detrimental consequences [1].
• In contrast, acetyl-LDL (matched for degradation with LDL) caused marked stimulation of ACAT activity in mouse peritoneal macrophages [9].

Chemical compound and disease context of Soat1

• Other compounds reported to inhibit ACAT, namely progesterone (20 microgram/mL) and N-acetyl-D-sphingosine (c(2)-ceramide, 10 microgram/mL), induced cellular toxicity in J774 macrophage foam cells and FC crystallization when coincubated with CPT-cAMP [10].
• Treatment of the foam cells with the acyl coenzyme-A:cholesterol acyltransferase (ACAT) inhibitor, CP-113,818, in the absence of any extracellular cholesterol acceptors, resulted in cellular toxicity [11].

Biological context of Soat1

• Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes esterification of cellular cholesterol [12].
• Some of these candidate genes are located within previously defined chromosomal regions (quantitative trait loci, QTLs) contributing to plasma lipoprotein levels, and Acact maps near a mouse mutation, ald, resulting in depletion of cholesteryl esters in the adrenals [13].
• Cellular cholesterol accumulation via incubation with acetylated LDL led to an increase in HDL binding sites as well as an increase in the activity of the cytoplasmic cholesterol esterifying enzyme acyl-CoA:cholesterol acyltransferase (ACAT) [14].
• Using the cDNA as a hybridization probe, we mapped the gene encoding mouse ACAT to chromosome 1 in a region syntenic to human chromosome 1 where the ACAT gene is located [3].
• Analysis of Acact cDNA from AKR mice revealed a deletion of the first coding exon and two missense mutations [15].

Anatomical context of Soat1

• However, the lesions in ACAT1-deficient mice were atypical in composition, with reduced amounts of neutral lipids and a paucity of macrophages in advanced lesions [1].
• One of these enzymes, ACAT1, is highly expressed in macrophages in atherosclerotic lesions, where it contributes to foam-cell formation [1].
• ACAT activity in the membrane fractions prepared from mouse liver and Caco-2 cells was also inhibited, indicating that the beauveriolides block both ACAT-1 and -2 [16].
• ACAT activities were present in the liver and intestine but were completely absent in adrenal, testes, ovaries, and peritoneal macrophages in our ACAT-1-/- mice [12].
• The ACAT-1-/- mice had decreased openings of the eyes because of atrophy of the meibomian glands, a modified form of sebaceous glands normally expressing high ACAT activities [12].

Associations of Soat1 with chemical compounds

• ACAT1 deficiency did not prevent the development of atherosclerotic lesions in either apoE-deficient or LDLR-deficient mice, despite causing relatively lower serum cholesterol levels [1].
• The objective of the present study was to determine whether a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, pactimibe sulfate (CS-505), could reduce atherosclerotic lesions beyond and independent of the reduction achieved by cholesterol lowering alone from two different types of lesions [17].
• ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice [17].
• We measured acyl-coenzyme A:cholesterol acyltransferase (ACAT) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activities in liver microsomes [18].
• Addition of the acyl coenzyme A:cholesterol acyltransferase inhibitor DuP 128 to cells incubated with the pHA-modified lipoproteins decreased cellular CE by 100%, 82%, and 95%, respectively, but had no effect on cellular triglycerides [19].

Regulatory relationships of Soat1

• Role of acyl-coenzyme A:cholesterol acyltransferase-1 in the control of hepatic very low density lipoprotein secretion and low density lipoprotein receptor expression in the mouse and hamster [20].
• Despite a lower level of ACAT activity, the ACAT1-expressing cells esterified 4-fold more sitosterol than the ACAT2 cells [21].

Other interactions of Soat1

• Treatment of cells with HMG-CoA reductase inhibitors enhanced N-CEase activity, whereas ACAT inhibitor decreased the activity [22].
• Free cholesterol deposition in the cornea of human apolipoprotein A-II transgenic mice with functional lecithin: cholesterol acyltransferase deficiency [23].
• Methods and RESULTS:ApoE-deficient mice were maintained for 17 weeks on a Western-type diet without (control) or with the ACAT inhibitor F-1394 (effective against ACAT1 and ACAT2) at doses of either 300 (low) or 900 (high) mg/kg [24].
• Hepatic enzyme activity of cholesterol-7 alpha-hydroxylase was elevated (P < 0.001) by treatment with B while activities of other hepatic enzymes were depressed, e.g., acyl-CoA cholesterol acyltransferase [25].
• Cholesteryl esters (CE) in lipid droplets undergo a continual cycle of hydrolysis and reesterification by neutral cholesterol esterase (N-CEase) and acyl CoA:cholesterol acyltransferase (ACAT), respectively [22].

Analytical, diagnostic and therapeutic context of Soat1

• Here we have examined the effect of oral administration of an ACAT inhibitor, F-1394, on atherosclerosis in apoE/LDLr-DKO mice fed a regular chow diet [26].
• The HF/HC diet had little effect on ACAT mRNA levels in the small intestine, aorta, adrenal, or peritoneal macrophages, whereas hepatic ACAT mRNA levels were doubled in mice fed the atherogenic diet [3].
• Immunoblotting of preputial gland homogenates demonstrated that AKR mice had an ACAT protein with a lower molecular mass than other mouse strains [15].
• Northern blot analysis and RNase protection assays of mouse tissues revealed that ACAT mRNA is expressed most highly in the adrenal gland, ovary, and preputial gland and is least abundant in skeletal muscle, adipose tissue, heart, and brain [3].
• The hepatic HMG-CoA reductase activity was significantly lower in the naringin and lovastatin supplemented groups than in the control group, whereas the ACAT activity was unaffected [27].

References