Disease relevance of SOAT2

• Infection of H5 insect cells with an ACAT-2 recombinant baculovirus resulted in expression of a approximately 46-kDa protein in cell membranes that was associated with high levels of cholesterol esterification activity [1].
• Structure of the human acyl-CoA:cholesterol acyltransferase-2 (ACAT-2) gene and its relation to dyslipidemia [2].
• In such cases, ACAT2 is an appealing target for therapy to reduce coronary heart disease [3].
• Acyl-CoA: cholesterol acyltransferase-2 (ACAT2), an intracellular cholesterol esterification enzyme found only in the intestine and liver, has been demonstrated to be associated with hypercholesterolemia and atherosclerosis in mice [4].
• In the hepatoma cell line HepG2 the CDX2 expression is elevated, accounting for its elevated ACAT2 expression [5].

High impact information on SOAT2

• Possible strategies focused on selective ACAT 2 inhibition or the combination of ACAT inhibitors with compounds that stimulate reverse cholesterol transport may prove to have clinical benefit [6].
• Overexpression of ACAT2 had a significantly greater impact upon assembly and secretion of VLDL from liver cells than did overexpression of ACAT1 [7].
• The addition of oleic acid (OA) to media resulted in a further increase in VLDL secretion from cells expressing DGAT1, ACAT1, or ACAT2 [7].
• Almost no cholesterol esterification was found when liver and intestinal microsomes from ACAT2 -/- mice were assayed [8].
• In adult intestines, most of the ACAT activity can be immunodepleted by anti-ACAT-2 [9].

Biological context of SOAT2

• ARGP2 is therefore a tissue-specific sterol esterification enzyme which we thus designated ACAT2 [10].
• In contrast to ACAT1 and similar to liver esterification, the activity of ARGP2 was relatively resistant to a histidine active site modifier [10].
• The mouse ACAT-2 gene (Acact2) maps to chromosome 15 in a region containing a quantitative trait locus influencing plasma cholesterol levels [1].
• The human ACAT-2 gene spans over 18 kb and contains 15 exons [11].
• The discovery of two isoforms of the enzyme, namely ACAT1 and ACAT2, with different substrate specificity and different potential function, offers a precious information for planning selective inhibitors with reduced secondary effects [12].

Anatomical context of SOAT2

• ARGP1 was expressed in numerous human adult tissues and tissue culture cell lines, whereas expression of ARGP2 was more restricted [10].
• ACAT-1 is more involved in macrophage foam cell formation and ACAT-2 plays a critical role in the cholesterol absorption process in intestinal enterocytes [13].
• In differentiating intestinal enterocyte-like Caco-2 cells, ACAT-2 protein content increases by 5-10-fold in 6 days, whereas ACAT-1 protein content remains relatively constant [9].
• In contrast, ACAT-2 is evident in fetal but not adult hepatocytes [9].
• Immunological quantitation and localization of ACAT-1 and ACAT-2 in human liver and small intestine [9].

Associations of SOAT2 with chemical compounds

• ACAT1 and ACAT2 membrane topology segregates a serine residue essential for activity to opposite sides of the endoplasmic reticulum membrane [14].
• Although further studies are needed, our data suggest that ACAT-2 may contribute to apoC-III gene expression and the assembly of apoC-III and TG, possibly in the intestine [2].
• Pactimibe exhibited dual inhibition for ACAT1 and ACAT2 (concentrations inhibiting 50% [IC50s] at micromolar levels) more potently than avasimibe [15].
• In contrast, HepG2 and ACAT2 microsomes utilized linolenoyl CoA as well [16].
• Incubation of oleic acid, arachidonic acid, or eicosapentaenoic acid, but not 25-hydroxycholesterol, induced ACAT1 mRNA levels 1.5--2-fold in HepG2, with no affect on ACAT2 mRNA [16].

Other interactions of SOAT2

• In vitro microsomal assays in a yeast strain deleted for both esterification genes and completely deficient in sterol esterification indicated that ARGP2 esterified cholesterol while ARGP1 did not [10].

Analytical, diagnostic and therapeutic context of SOAT2

• Next, 187 (91 dyslipidemic and 96 normolipidemic) subjects were screened by PCR single-strand conformational polymorphism analysis of the ACAT-2 gene [2].
• In congenital hyperlipidemic mice, immunohistochemistry and RT-PCR demonstrated that ACAT2 was also present in lipid-laden cells of the atheromatous plaques [17].
• The expressed hACAT-1 and hACAT-2 appeared as a 50 kDa- and a 46 kDa-band on SDS-PAGE, respectively, from Hi5 cells and they preferred to exist in oligomeric form, from dimer to tetramer, during the purification process [18].
• Results of luciferase reporter and electrophoretic mobility shift assays show that CDX2 and HNF1alpha exert a synergistic effect, enhancing the ACAT2 promoter activity through binding to these cis-elements [5].

References