Disease relevance of SOAT1

• Among the 10 mutants generated by baculovirus expression technology, H386A-ACAT1, H460A-ACAT1, H360A-ACAT2, and H399A-ACAT2 lost their enzymatic activity completely [1].
• ACAT inhibition reverses LCAT deficiency and improves plasma HDL in chronic renal failure [2].
• In view of the above considerations, we tested the hypothesis that pharmacological inhibition of ACAT may ameliorate CRF-induced dyslipidemia [2].
• This review paper will focus on the role of ACAT in cholesterol metabolism, in particular as a target to develop novel therapeutic agents to control hypercholesterolemia, atherosclerosis, and Alzheimer's disease [3].
• It is believed that ACAT plays a key role in lipoprotein metabolism and atherogenesis [4].

Psychiatry related information on SOAT1

• This polymorphism of SOAT1 is also associated with reduced risk for Alzheimer's disease in ethnically distinct populations (P=0.0001, odds ratio: 0.6, 95% confidence interval 0.4-0.8) [5].
• The "stat" group was referred more often for the management of behavior and suicide risk evaluation, and received more diagnoses of organic mental disorders than the other referrals [6].
• Forty-seven per cent of patients received "stat" intravenous thiamine (although the Wernicke-Korsakoff syndrome is rare) [7].
• Here, as a means of reviewing the use of such tests and as an aid in decision making, is a break down of the probability of stat testing based on Diagnosis-related Group categories [8].

High impact information on SOAT1

• In addition, we present a working model linking the presumed allosteric property of ACAT with cholesterol trafficking into and out of the endoplasmic reticulum [9].
• The topics reviewed in this chapter include the pathophysiological roles of ACAT, the biochemistry and molecular biology of the ACAT protein and the ACAT gene, and the mode of regulation by sterol or nonsterol agents in mammalian cells [9].
• Due to its presumed role in regulating cellular cholesterol homeostasis, and in various pathophysiological conditions, acyl-coenzyme A:cholesterol acyltransferase (ACAT) has attracted much attention [9].
• When cholesterol-loaded macrophages are incubated in medium containing plasma, cholesterol moves from the cells to HDL and is then esterified by lecithin/cholesterol acyltransferase [10].
• In human cells, sterol is esterified to a storage form by acyl-coenzyme A (CoA): cholesterol acyl transferase (ACAT) [11].

Chemical compound and disease context of SOAT1

• Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer's disease [5].
• In this report we examine the macrophage ACAT reactivity of the shellfish sterol, desmosterol, and other sterols found in man because of shellfish ingestion or in association with the foam cell diseases sitosterolemia and cerebrotendinous xanthomatosis (CTX) [12].
• The adenine pool of the macrophages was radiolabeled prior to addition of the ACAT inhibitors, in order to monitor the release of radiolabeled adenine, a technique shown to be a sensitive method to monitor drug-induced toxicity [13].
• In this sense, beta-lactams can serve as inhibitors of serine proteases, such as human leukocyte elastase (HLE) or thrombin, acyl-CoA cholesterol acyltransferase inhibitors and inhibitors of human cytomegalovirus [14].
• Acylcoenzyme A:cholesterol acyltransferase (ACAT) was solubilized from Ehrlich ascites cell microsomes with Triton X-100 [15].

Biological context of SOAT1

• To develop more potent hACAT inhibitor, shikonin derivatives (5-11) were synthesized by semi-synthesis of shikonin (4), which was prepared by hydrolysis of 1-3 [16].
• Acyl-CoA: cholesterol acyltransferase (ACAT) plays an important role in the esterification of cholesterol with its substrates, cholesterol and fatty acyl coenzyme A, to facilitate both intracellular storage and intercellular transport [17].
• ACAT (also called sterol o-acyltransferase) catalyzes the esterification of cholesterol by reaction with long-chain acyl-CoA derivatives and plays a pivotal role in the regulation of cholesterol homeostasis [18].
• These results demonstrate that the histidine residues located at the active site are very crucial both for the catalytic activity of the enzyme and for distinguishing ACAT1 from ACAT2 with respect to enzyme catalysis and substrate specificity [1].
• To investigate a role for histidine residues in the expression of normal acyl-CoA:cholesterol acyltransferase (ACAT) activity, the histidine residues located at five different positions in two isoenzymes were substituted by alanine, based on the sequence homology between ACAT1 and ACAT2 [1].

Anatomical context of SOAT1

• However, it is not yet known whether 5-HT affects ACAT-1 expression in human monocyte-macrophages as the molecular mechanism of enhanced foam cell formation by 5-HT remains unclear [19].
• 5-HT increased ACAT activity in a concentration-dependent manner after 7 days in primary monocyte culture [19].
• To further elucidate the mechanism for ACAT-1 regulation in macrophages, we examined the effects of five cytokines including transforming growth factor-beta1 (TGF- beta1) on ACAT-1 expression in cultured human monocyte-macrophages [20].
• We further show that the activation is not due to an increase in ACAT1 protein content, but is partly due to an increase in the cholesterol content in the endoplasmic reticulum where ACAT1 resides [21].
• Additionally, enantiomeric cholesterol, which has the same biophysical properties as cholesterol in membranes, fails to activate ACAT1 [21].

Associations of SOAT1 with chemical compounds

• Acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) converts intracellular free cholesterol into cholesterol ester for storage in lipid droplets and plays an important role in the formation of macrophage-derived foam cells in atherosclerotic lesions [19].
• Serotonin acts as an up-regulator of acyl-coenzyme A:cholesterol acyltransferase-1 in human monocyte-macrophages [19].
• Pactimibe exhibited dual inhibition for ACAT1 and ACAT2 (concentrations inhibiting 50% [IC50s] at micromolar levels) more potently than avasimibe [22].
• Importance of acyl-coenzyme A:cholesterol acyltransferase 1/2 dual inhibition for anti-atherosclerotic potency of pactimibe [22].
• Pactimibe sulfate, [7-(2,2-dimethylpropanamido)-4,6-dimethyl-1-octylindolin-5-yl]acetic acid hemisulfate, a novel Acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitor, was investigated in vitro and in vivo to characterize its potential [22].

Regulatory relationships of SOAT1

• Since TGF-beta1 is expressed in human atherosclerotic lesions, the current results suggest that ACAT-1 expression in monocytes infiltrating from the circulation to vascular walls may be enhanced by pre-existing TGF-beta1 [20].
• On the other hand, low stimulatory concentrations acted in a SMAD 3-independent pathway and activated STAT proteins [23].
• We inserted either the hemagglutinin tag or the HisT7 tag at various hydrophilic regions within the human ACAT-1 protein and used immunofluorescence microscopy to determine the topography of the tagged proteins expressed in mutant Chinese hamster ovary cells lacking endogenous ACAT [24].
• ApoA-I and apoC-I activate lecithin/cholesterol acyltransferase; apoC-II is an activator of lipoprotein lipase [25].
• Adiponectin down-regulates acyl-coenzyme A:cholesterol acyltransferase-1 in cultured human monocyte-derived macrophages [26].

Other interactions of SOAT1

• Immunoblot analyses showed that TGF-beta1 increased ACAT-1 protein expression by two- to threefold when added during differentiation of human monocytes into macrophages [20].
• To study ACAT2 topology, we inserted two different antigenic tags (hemagglutinin, monoclonal antibody Mab1) at various hydrophilic regions flanking each of its predicted TMDs, and expressed the recombinant proteins in mutant Chinese hamster ovary cells lacking endogenous ACAT [27].
• In adult intestines, most of the ACAT activity can be immunodepleted by anti-ACAT-2 [28].
• In conclusion, inhibition of ACAT reversed LCAT deficiency and improved plasma HDL level in CRF rats [2].
• AcylCoA:cholesterol acyltransferase (ACAT) and diacylglycerol acyltransferase (DGAT) activities measured on cell-free extracts appeared to be decreased also by phospholipid polar head group modification, whereas the overall phospholipid acyltransferase activity remained unchanged [29].

Analytical, diagnostic and therapeutic context of SOAT1

• Northern blotting analysis indicated that among the four ACAT-1 mRNA transcripts (2.8-, 3.6-, 4.3-, and 7.0-kb), the levels of the 2.8- and 3.6-kb transcripts were selectively up-regulated by approximately 1.7-fold by 5-HT (10 microM) [19].
• CONCLUSIONS: K-604, a potent and selective inhibitor of ACAT-1, suppressed the development of atherosclerosis in an animal model without affecting plasma cholesterol levels, providing direct evidence that pharmacological inhibition of ACAT-1 in the arterial walls leads to suppression of atherosclerosis [30].
• Molecular cloning and functional expression of human acyl-coenzyme A:cholesterol acyltransferase cDNA in mutant Chinese hamster ovary cells [31].
• We have now mapped the ACAT gene to chromosome 1, band q25 by using fluorescence in situ hybridization to metaphase chromosomes, and by Southern blotting analysis of human--hamster somatic cell hybrid panels [4].
• We also examined the effects of IL-7, PKC inhibitor, and STAT inhibitor on the expressions of TGF-beta1 and type I collagen alpha1 chain (col1A1) m-RNA by using real-time RT-PCR [32].

References