Alternative titles; symbols
HGNC Approved Gene Symbol: SOAT1
Cytogenetic location: 1q25.2 Genomic coordinates (GRCh38): 1:179,293,797-179,358,680 (from NCBI)
Acyl-coenzyme A:cholesterol acyltransferase (ACACT; EC 2.3.1.26) is an intracellular protein located in the endoplasmic reticulum that forms cholesterol esters from cholesterol. Accumulation of cholesterol esters as cytoplasmic lipid droplets within macrophages and smooth muscle cells is a characteristic feature of the early stages of atherosclerotic plaques (Cadigan et al., 1988).
Cadigan et al. (1988) isolated a cell line lacking ACACT activity from mutagenized Chinese hamster ovary cells. By DNA-mediated gene transfer into ACACT-deficient cells, Cadigan et al. (1989) obtained transfectant cells stably expressing human ACACT activity. Using genomic DNAs of these transfectant cells as starting materials, Chang et al. (1993) cloned a human macrophage cDNA encoding ACACT. The cDNA contained a single open reading frame of approximately 1.7 kb. Protein homology analysis of this ORF indicated that it represents a structural gene for ACACT.
Unesterified sterol modulates the function of eukaryotic membranes. In human cells, sterol is esterified to a storage form by acyl-CoA:cholesterol acyltransferase. Yang et al. (1996) identified 2 genes, which they designated ARE1 and ARE2, that encode related enzymes in yeast. The yeast enzymes are 49% identical to each other and exhibit 23% identity and 49% similarity to human sterol O-acyltransferase. A deletion of ARE2 reduced the sterol ester levels to approximately 25% of normal levels, whereas disruption of ARE1 did not affect sterol ester biosynthesis. Deletion of both genes resulted in a viable cell with undetectable esterified sterol. With the use of a consensus sequence to the yeast and human genes, an additional member of the SOAT gene family was identified in humans; see SOAT2; 601311.
Puglielli et al. (2001) found that beta-amyloid (APP; 104760) production was regulated by intracellular cholesterol compartmentation. Specifically, cytoplasmic cholesteryl esters, formed by acyl-CoA:cholesterol acyltransferase, were correlated with beta-amyloid production. In vitro studies showed that inhibition of SOAT1 reduced beta-amyloid generation, and the authors concluded that SOAT1 indirectly modulates beta-amyloid generation by controlling the equilibrium between free cholesterol and cytoplasmic cholesteryl esters. Hutter-Paier et al. (2004) found that pharmacologic inhibition of SOAT1 significantly reduced brain amyloid plaques, insoluble amyloid levels, and brain cholesteryl esters in a transgenic mouse model of Alzheimer disease (104300) generated by mutations in the APP gene. Spatial learning in the transgenic mice was slightly improved and correlated with decreased beta-amyloid levels.
ACAT esterifies cholesterol in a variety of tissues. In some animal models, ACAT inhibitors were found to be remarkably effective in reducing the formation of atheromas (Bocan et al., 2000); however, some studies involving genetically engineered mice have suggested that inhibition of ACAT1 may promote atherosclerosis (Accad et al., 2000; Fazio et al., 2001). Nissen et al. (2006) performed intravascular ultrasonography in 408 patients with angiographically documented coronary disease. All patients received usual care for secondary prevention, including statins, if indicated. Patients receiving an ACAT inhibitor were compared with patients receiving a placebo. Ultrasonography after 18 months showed that the inhibitor did not improve the primary measure of efficacy (percent atheroma volume) and adversely affected 2 major secondary efficacy measures assessed by intravascular ultrasonography. Nissen et al. (2006) concluded that ACAT inhibition is not an effective strategy for limiting atherosclerosis and may promote atherogenesis.
By fluorescence in situ hybridization and Southern blot analysis of human/hamster somatic cell hybrid panels, Chang et al. (1994) mapped the SOAT1 gene to chromosome 1q25.
The preferred symbol for this gene is SOAT1, for sterol O-acyltransferase-1. Some authors have used the abbreviation ACAT for the enzyme; this symbol, however, has been used for another enzyme with ketothiolase activity (ACAT1; 607809). Literature symbols used for this gene also include ACACT and STAT (not to be confused with a family of signal transducer/transcription activator genes; see 600555).
Meiner et al. (1996) noted that ACACT activity is found in many tissues, including macrophages, adrenal glands, and liver. In macrophages, ACACT is thought to participate in foam cell formation and thereby to contribute to the development of atherosclerotic lesions. Meiner et al. (1996) disrupted the homologous gene (Acact) in mice, which resulted in decreased cholesterol esterification in Acact-deficient fibroblasts and adrenal membranes and markedly reduced cholesterol ester levels in adrenal glands and peritoneal macrophages. In contrast, the livers of Acact-deficient mice contained substantial amounts of cholesterol esters and exhibited no reduction in cholesterol esterification activity. These tissue-specific reductions in cholesterol esterification provided evidence that in mammals this process involves more than 1 form of esterification enzyme.
Ald, a recessive allele in AKR inbred mice, is responsible for complete adrenocortical lipid depletion in postpubertal males, which appears to be androgen dependent. Crossing Acact -/- mice with AKR (ald/ald) mice yielded postpubertal male offspring characterized by adrenocortical lipid depletion, indicating that these loci are not complementational and are therefore allelic. Immunoblotting of preputial gland homogenates demonstrated that AKR mice had an ACACT protein with a lower molecular mass than other mouse strains. Analysis of Acact cDNA from AKR mice revealed a deletion of the first coding exon and 2 missense mutations. Despite these coding sequence differences, the ACACT protein from the Ald allele catalyzed cholesterol esterification activity at levels similar to that of wildtype protein. Meiner et al. (1998) speculated that the adrenocortical lipid depletion resulting from the ald mutation is caused by an altered susceptibility of the mutant protein to modifying factors, such as androgen production at puberty, in an undetermined manner.
Accad, M., Smith, S. J., Newland, D. L., Sanan, D. A., King, L. E., Jr., Linton, M. F., Fazio, S., Farese, R. V., Jr. Massive xanthomatosis in altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1. J. Clin. Invest. 105: 711-719, 2000. [PubMed: 10727439] [Full Text: https://doi.org/10.1172/JCI9021]
Bocan, T. M. A., Krause, B. R., Rosebury, W. S., Mueller, S. B., Lu, X., Dagle, C., Major, T., Lathia, C., Lee, H. The ACAT inhibitor avasimibe reduces macrophages and matrix metalloproteinase expression in atherosclerotic lesions of hypercholesterolemic rabbits. Arterioscler. Thromb. Vasc. Biol. 20: 70-79, 2000. [PubMed: 10634802] [Full Text: https://doi.org/10.1161/01.atv.20.1.70]
Cadigan, K. M., Chang, C. C. Y., Chang, T.-Y. Isolation of Chinese hamster ovary cell lines expressing human acyl-coenzyme A/cholesterol acyltransferase activity. J. Cell Biol. 108: 2201-2210, 1989. [PubMed: 2738092] [Full Text: https://doi.org/10.1083/jcb.108.6.2201]
Cadigan, K. M., Heider, J. G., Chang, T.-Y. Isolation and characterization of Chinese hamster ovary cell mutants deficient in acyl-coenzyme A:cholesterol acyltransferase activity. J. Biol. Chem. 263: 274-282, 1988. [PubMed: 3335499]
Chang, C. C. Y., Huh, H. Y., Cadigan, K. M., Chang, T. Y. Molecular cloning and functional expression of human acyl-coenzyme A:cholesterol acyltransferase cDNA in mutant Chinese hamster ovary cells. J. Biol. Chem. 268: 20747-20755, 1993. [PubMed: 8407899]
Chang, C. C. Y., Noll, W. W., Nutile-McMenemy, N., Lindsay, E. A., Baldini, A., Chang, W., Chang, T. Y. Localization of acyl coenzyme A:cholesterol acyltransferase gene to human chromosome 1q25. Somat. Cell Molec. Genet. 20: 71-74, 1994. [PubMed: 8197480] [Full Text: https://doi.org/10.1007/BF02257489]
Fazio, S., Major, A. S., Swift, L. L., Gleaves, L. A., Accad, M., Linton, M. F., Farese, R. V., Jr. Increased atherosclerosis in LDL receptor-null mice lacing ACAT1 in macrophages. J. Clin. Invest. 107: 163-171, 2001. [PubMed: 11160132] [Full Text: https://doi.org/10.1172/JCI10310]
Hutter-Paier, B., Huttunen, H. J., Puglielli, L., Eckman, C. B., Kim, D. Y., Hofmeister, A., Moir, R. D., Domnitz, S. B., Frosch, M. P., Windisch, M., Kovacs, D. M. The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease. Neuron 44: 227-238, 2004. Note: Erratum: Neuron 68: 1014 only, 2010. [PubMed: 15473963] [Full Text: https://doi.org/10.1016/j.neuron.2004.08.043]
Meiner, V. L., Cases, S., Myers, H. M., Sande, E. R., Bellosta, S., Schambelan, M., Pitas, R. E., McGuire, J., Herz, J., Farese, R. V., Jr. Disruption of the acyl-CoA:cholesterol acyltransferase gene in mice: evidence suggesting multiple cholesterol esterification enzymes in mammals. Proc. Nat. Acad. Sci. 93: 14041-14046, 1996. [PubMed: 8943057] [Full Text: https://doi.org/10.1073/pnas.93.24.14041]
Meiner, V. L., Welch, C. L., Cases, S., Myers, H. M., Sande, E., Lusis, A. J., Farese, R. V., Jr. Adrenocortical lipid depletion gene (ald) in AKR mice is associated with an acyl-CoA:cholesterol acyltransferase (ACAT) mutation. J. Biol. Chem. 273: 1064-1069, 1998. [PubMed: 9422770] [Full Text: https://doi.org/10.1074/jbc.273.2.1064]
Nissen, S. E., Tuzcu, E. M., Brewer, H. B., Sipahi, I., Nicholls, S. J., Ganz, P., Schoenhagen, P., Waters, D. D., Pepine, C. J., Crowe, T. D., Davidson, M. H., Deanfield, J. E., Wisniewski, L. M., Hanyok, J. J., Kassalow, L. M. Effect of ACAT inhibition on the progression of coronary atherosclerosis. New Eng. J. Med. 354: 1253-1263, 2006. Note: Erratum: New Eng. J. Med. 355: 638 only, 2006. [PubMed: 16554527] [Full Text: https://doi.org/10.1056/NEJMoa054699]
Puglielli, L., Konopka, G., Pack-Chung, E., MacKenzie Ingano, L. A., Berezovska, O., Hyman, B. T., Chang, T. Y., Tanzi, R. E., Kovacs, D. M. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid beta-peptide. Nature Cell Biol. 3: 905-912, 2001. [PubMed: 11584272] [Full Text: https://doi.org/10.1038/ncb1001-905]
Yang, H., Bard, M., Bruner, D. A., Gleeson, A., Deckelbaum, R. J., Aljinovic, G., Pohl, T. M., Rothstein, R., Sturley, S. L. Sterol esterification in yeast: a two-gene process. Science 272: 1353-1356, 1996. [PubMed: 8650549] [Full Text: https://doi.org/10.1126/science.272.5266.1353]