Inmacrophages,theaccumulationofcholesterylesterssynthesizedbytheactivatedacyl-coenzymeA:cholesterolacyltransferase-1(ACAT1)resultsinthefoamcellformation,ahallmarkofearlyatheroscleroticlesions.Inthisstudy,withthetreatmentofaglucocorticoidhormonedexamethasone(Dex),lipidstainingresultsclearlyshowedthelargeaccumulationoflipiddropletscontainingcholesterylestersinTHP-1-derivedmacrophagesexposedtolowerconcentrationoftheoxidizedlow-densitylipoprotein(ox-LDL).Morenotably,whentreatedtogetherwithspecificanti-ACATinhibitors,theabundantcholesterylesteraccumulationwasmarkedlydiminishedinTHP-l-derivedmacrophages,confirmingthatACATisthekeyenzymeresponsibleforintracellularcholesterylestersynthesis.RT-PCRandWesternblotresultsindicatedthatDexcausedup-regulationofhumanACAT1expressionatboththemRNAandproteinlevelsinTHP-1andTHP-1-derivedmacrophages.TheluciferaseactivityassaydemonstratedthatDexcouldenhancetheactivityofhumanACAT1geneP1promoter,amajorfactorleadingtotheACAT1activation,inacell-specificmanner.Furtherexperimentalevidencesshowedthataglucocorticoidresponseelement(GRE)locatedwithinhumanACAT1geneP1promotertoresponsetotheelevationofhumanACAT1geneexpressionbyDexcouldbefunctionallyboundwithglucocorticoidreceptor(GR)proteins.ThesedatasupportedthehypothesisthattheclinicaltreatmentwithDex,whichincreasedtheincidenceofatherosclerosis,mayinpartduetoenhancingtheACAT1expressiontopromotetheaccumulationofcholesterylestersduringthemacrophage-derivedfoamcellformation,anearlystageofatherosclerosis.
