Enhancement of human ACAT1 gene expression to promote the macrophage-derived foam cell formation by dexamethasone
ABSTRACT In macrophages, the accumulation of cholesteryl esters synthesized by the activated acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) results in the foam cell formation, a hallmark of early atherosclerotic lesions. In this study, with the treatment of a glucocorticoid hormone dexamethas...
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| Veröffentlicht in: | Cell research 2004-08, Vol.14 (4), p.315-323 |
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| creator | YANG, Li YANG, Jin Bo CHEN, Jia YU, Guang Yao ZHOU, Pei LEI, Lei WANG, Zhen Zhen CHANG, Catherine CY YANG, Xin Ying CHANG, Ta Yuan LI, Bo Liang |
| description | ABSTRACT
In macrophages, the accumulation of cholesteryl esters synthesized by the activated acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) results in the foam cell formation, a hallmark of early atherosclerotic lesions. In this study, with the treatment of a glucocorticoid hormone dexamethasone (Dex), lipid staining results clearly showed the large accumulation of lipid droplets containing cholesteryl esters in THP-1-derived macrophages exposed to lower concentration of the oxidized low-density lipoprotein (ox-LDL). More notably, when treated together with specific anti-ACAT inhibitors, the abundant cholesteryl ester accumulation was markedly diminished in THP-1-derived macrophages, confirming that ACAT is the key enzyme responsible for intracellular cholesteryl ester synthesis. RT-PCR and Western blot results indicated that Dex caused up-regulation of human ACAT1 expression at both the mRNA and protein levels in THP-1 and THP-1-derived macrophages. The luciferase activity assay demonstrated that Dex could enhance the activity of human ACAT1 gene P1 promoter, a major factor leading to the ACAT1 activation, in a cell-specific manner. Further experimental evidences showed that a glucocorticoid response element (GRE) located within human ACAT1 gene P1 promoter to response to the elevation of human ACAT1 gene expression by Dex could be functionally bound with glucocorticoid receptor (GR) proteins. These data supported the hypothesis that the clinical treatment with Dex, which increased the incidence of atherosclerosis, may in part due to enhancing the ACAT1 expression to promote the accumulation of cholesteryl esters during the macrophage-derived foam cell formation, an early stage of atherosclerosis. |
| doi_str_mv | 10.1038/sj.cr.7290231 |
| format | Article |
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In macrophages, the accumulation of cholesteryl esters synthesized by the activated acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) results in the foam cell formation, a hallmark of early atherosclerotic lesions. In this study, with the treatment of a glucocorticoid hormone dexamethasone (Dex), lipid staining results clearly showed the large accumulation of lipid droplets containing cholesteryl esters in THP-1-derived macrophages exposed to lower concentration of the oxidized low-density lipoprotein (ox-LDL). More notably, when treated together with specific anti-ACAT inhibitors, the abundant cholesteryl ester accumulation was markedly diminished in THP-1-derived macrophages, confirming that ACAT is the key enzyme responsible for intracellular cholesteryl ester synthesis. RT-PCR and Western blot results indicated that Dex caused up-regulation of human ACAT1 expression at both the mRNA and protein levels in THP-1 and THP-1-derived macrophages. The luciferase activity assay demonstrated that Dex could enhance the activity of human ACAT1 gene P1 promoter, a major factor leading to the ACAT1 activation, in a cell-specific manner. Further experimental evidences showed that a glucocorticoid response element (GRE) located within human ACAT1 gene P1 promoter to response to the elevation of human ACAT1 gene expression by Dex could be functionally bound with glucocorticoid receptor (GR) proteins. These data supported the hypothesis that the clinical treatment with Dex, which increased the incidence of atherosclerosis, may in part due to enhancing the ACAT1 expression to promote the accumulation of cholesteryl esters during the macrophage-derived foam cell formation, an early stage of atherosclerosis.</description><identifier>ISSN: 1001-0602</identifier><identifier>EISSN: 1748-7838</identifier><identifier>DOI: 10.1038/sj.cr.7290231</identifier><identifier>PMID: 15353128</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Accumulation ; Arteriosclerosis - chemically induced ; Arteriosclerosis - metabolism ; Arteriosclerosis - physiopathology ; Base Sequence ; Biomedical and Life Sciences ; Cell Biology ; Cell Line ; Cholesterol ; Cholesterol Esters - metabolism ; Cholesterol, LDL - metabolism ; Cholesterol, LDL - pharmacology ; Dexamethasone - pharmacology ; Enzyme Inhibitors - pharmacology ; Esters ; Foam Cells - drug effects ; Foam Cells - physiology ; Gene Expression Regulation - drug effects ; Glucocorticoids - pharmacology ; Humans ; Lesions ; Life Sciences ; Macrophages - drug effects ; Macrophages - physiology ; Molecular Sequence Data ; Promoter Regions, Genetic - drug effects ; Receptors, Glucocorticoid - drug effects ; Receptors, Glucocorticoid - metabolism ; Response Elements - drug effects ; RNA, Messenger - drug effects ; RNA, Messenger - metabolism ; Sterol O-Acyltransferase - drug effects ; Sterol O-Acyltransferase - genetics ; Sterol O-Acyltransferase - metabolism ; Up-Regulation - drug effects</subject><ispartof>Cell research, 2004-08, Vol.14 (4), p.315-323</ispartof><rights>Science Press 2004</rights><rights>Copyright Nature Publishing Group Aug 2004</rights><rights>Copyright © Wanfang Data Co. Ltd. All Rights Reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c458t-a4807e23006c63c32a99f074f77ba1e061a69b9695eda8ee2c4a9a8c6da44ff3</citedby><cites>FETCH-LOGICAL-c458t-a4807e23006c63c32a99f074f77ba1e061a69b9695eda8ee2c4a9a8c6da44ff3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.wanfangdata.com.cn/images/PeriodicalImages/xbyj/xbyj.jpg</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/sj.cr.7290231$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/sj.cr.7290231$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,777,781,27905,27906,41469,42538,51300</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15353128$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>YANG, Li</creatorcontrib><creatorcontrib>YANG, Jin Bo</creatorcontrib><creatorcontrib>CHEN, Jia</creatorcontrib><creatorcontrib>YU, Guang Yao</creatorcontrib><creatorcontrib>ZHOU, Pei</creatorcontrib><creatorcontrib>LEI, Lei</creatorcontrib><creatorcontrib>WANG, Zhen Zhen</creatorcontrib><creatorcontrib>CHANG, Catherine CY</creatorcontrib><creatorcontrib>YANG, Xin Ying</creatorcontrib><creatorcontrib>CHANG, Ta Yuan</creatorcontrib><creatorcontrib>LI, Bo Liang</creatorcontrib><title>Enhancement of human ACAT1 gene expression to promote the macrophage-derived foam cell formation by dexamethasone</title><title>Cell research</title><addtitle>Cell Res</addtitle><addtitle>Cell Res</addtitle><description>ABSTRACT
In macrophages, the accumulation of cholesteryl esters synthesized by the activated acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) results in the foam cell formation, a hallmark of early atherosclerotic lesions. In this study, with the treatment of a glucocorticoid hormone dexamethasone (Dex), lipid staining results clearly showed the large accumulation of lipid droplets containing cholesteryl esters in THP-1-derived macrophages exposed to lower concentration of the oxidized low-density lipoprotein (ox-LDL). More notably, when treated together with specific anti-ACAT inhibitors, the abundant cholesteryl ester accumulation was markedly diminished in THP-1-derived macrophages, confirming that ACAT is the key enzyme responsible for intracellular cholesteryl ester synthesis. RT-PCR and Western blot results indicated that Dex caused up-regulation of human ACAT1 expression at both the mRNA and protein levels in THP-1 and THP-1-derived macrophages. The luciferase activity assay demonstrated that Dex could enhance the activity of human ACAT1 gene P1 promoter, a major factor leading to the ACAT1 activation, in a cell-specific manner. Further experimental evidences showed that a glucocorticoid response element (GRE) located within human ACAT1 gene P1 promoter to response to the elevation of human ACAT1 gene expression by Dex could be functionally bound with glucocorticoid receptor (GR) proteins. These data supported the hypothesis that the clinical treatment with Dex, which increased the incidence of atherosclerosis, may in part due to enhancing the ACAT1 expression to promote the accumulation of cholesteryl esters during the macrophage-derived foam cell formation, an early stage of atherosclerosis.</description><subject>Accumulation</subject><subject>Arteriosclerosis - chemically induced</subject><subject>Arteriosclerosis - metabolism</subject><subject>Arteriosclerosis - physiopathology</subject><subject>Base Sequence</subject><subject>Biomedical and Life Sciences</subject><subject>Cell Biology</subject><subject>Cell Line</subject><subject>Cholesterol</subject><subject>Cholesterol Esters - metabolism</subject><subject>Cholesterol, LDL - metabolism</subject><subject>Cholesterol, LDL - pharmacology</subject><subject>Dexamethasone - pharmacology</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Esters</subject><subject>Foam Cells - drug effects</subject><subject>Foam Cells - physiology</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Glucocorticoids - pharmacology</subject><subject>Humans</subject><subject>Lesions</subject><subject>Life Sciences</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - physiology</subject><subject>Molecular Sequence Data</subject><subject>Promoter Regions, Genetic - drug effects</subject><subject>Receptors, Glucocorticoid - drug effects</subject><subject>Receptors, Glucocorticoid - metabolism</subject><subject>Response Elements - drug effects</subject><subject>RNA, Messenger - drug effects</subject><subject>RNA, Messenger - metabolism</subject><subject>Sterol O-Acyltransferase - drug effects</subject><subject>Sterol O-Acyltransferase - genetics</subject><subject>Sterol O-Acyltransferase - metabolism</subject><subject>Up-Regulation - drug effects</subject><issn>1001-0602</issn><issn>1748-7838</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpt0U2L2zAQBmCztOxXe-y1CEr35nQky5Z8DGF3W1joJXczlsdxTCRlJbtN_n0VEtpSig4S6NE7jCbLPnBYcCj0lzguTFgoUYMo-FV2y5XUudKFfpPOADyHCsRNdhfjCCBKWfLr7IaXRVlwoW-z10c3oDNkyU3M92yYLTq2XC3XnG3IEaPDPlCMW-_Y5Nk-eOsnYtNAzKIJfj_ghvKOwvYHdaz3aJmh3S6dgsXp9Ko9so4OaGkaMHpH77K3Pe4ivb_s99n66XG9-pq_fH_-tlq-5EaWespRalAkCoDKVIUpBNZ1D0r2SrXICSqOVd3WVV1Sh5pIGIk1alN1KGXfF_fZ53PsT3Q9uk0z-jm4VLA5tMdRAMi0oEru4exSa68zxamx23hqAR35OTZcqVpqWSb46R_4O5GDUEpXAuqk8rNKfxNjoL7Zh63FcEyoOQ2siWNjQnMZWPIfL6lza6n7oy8TSmBxBjFduQ2Fv8v-L_EXSleg_A</recordid><startdate>20040801</startdate><enddate>20040801</enddate><creator>YANG, Li</creator><creator>YANG, Jin Bo</creator><creator>CHEN, Jia</creator><creator>YU, Guang Yao</creator><creator>ZHOU, Pei</creator><creator>LEI, Lei</creator><creator>WANG, Zhen Zhen</creator><creator>CHANG, Catherine CY</creator><creator>YANG, Xin Ying</creator><creator>CHANG, Ta Yuan</creator><creator>LI, Bo Liang</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><general>State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, 320 Yueyang Road Shanghai 200031, China%Department of Biochemistry, Dartmouth Medical School, Hanover, NH 03756, USA</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QO</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope><scope>2B.</scope><scope>4A8</scope><scope>92I</scope><scope>93N</scope><scope>PSX</scope><scope>TCJ</scope></search><sort><creationdate>20040801</creationdate><title>Enhancement of human ACAT1 gene expression to promote the macrophage-derived foam cell formation by dexamethasone</title><author>YANG, Li ; YANG, Jin Bo ; CHEN, Jia ; YU, Guang Yao ; ZHOU, Pei ; LEI, Lei ; WANG, Zhen Zhen ; CHANG, Catherine CY ; YANG, Xin Ying ; CHANG, Ta Yuan ; LI, Bo Liang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c458t-a4807e23006c63c32a99f074f77ba1e061a69b9695eda8ee2c4a9a8c6da44ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Accumulation</topic><topic>Arteriosclerosis - chemically induced</topic><topic>Arteriosclerosis - metabolism</topic><topic>Arteriosclerosis - physiopathology</topic><topic>Base Sequence</topic><topic>Biomedical and Life Sciences</topic><topic>Cell Biology</topic><topic>Cell Line</topic><topic>Cholesterol</topic><topic>Cholesterol Esters - metabolism</topic><topic>Cholesterol, LDL - metabolism</topic><topic>Cholesterol, LDL - pharmacology</topic><topic>Dexamethasone - pharmacology</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Esters</topic><topic>Foam Cells - drug effects</topic><topic>Foam Cells - physiology</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Glucocorticoids - pharmacology</topic><topic>Humans</topic><topic>Lesions</topic><topic>Life Sciences</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - physiology</topic><topic>Molecular Sequence Data</topic><topic>Promoter Regions, Genetic - drug effects</topic><topic>Receptors, Glucocorticoid - drug effects</topic><topic>Receptors, Glucocorticoid - 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In macrophages, the accumulation of cholesteryl esters synthesized by the activated acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) results in the foam cell formation, a hallmark of early atherosclerotic lesions. In this study, with the treatment of a glucocorticoid hormone dexamethasone (Dex), lipid staining results clearly showed the large accumulation of lipid droplets containing cholesteryl esters in THP-1-derived macrophages exposed to lower concentration of the oxidized low-density lipoprotein (ox-LDL). More notably, when treated together with specific anti-ACAT inhibitors, the abundant cholesteryl ester accumulation was markedly diminished in THP-1-derived macrophages, confirming that ACAT is the key enzyme responsible for intracellular cholesteryl ester synthesis. RT-PCR and Western blot results indicated that Dex caused up-regulation of human ACAT1 expression at both the mRNA and protein levels in THP-1 and THP-1-derived macrophages. The luciferase activity assay demonstrated that Dex could enhance the activity of human ACAT1 gene P1 promoter, a major factor leading to the ACAT1 activation, in a cell-specific manner. Further experimental evidences showed that a glucocorticoid response element (GRE) located within human ACAT1 gene P1 promoter to response to the elevation of human ACAT1 gene expression by Dex could be functionally bound with glucocorticoid receptor (GR) proteins. These data supported the hypothesis that the clinical treatment with Dex, which increased the incidence of atherosclerosis, may in part due to enhancing the ACAT1 expression to promote the accumulation of cholesteryl esters during the macrophage-derived foam cell formation, an early stage of atherosclerosis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>15353128</pmid><doi>10.1038/sj.cr.7290231</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cell research, 2004-08, Vol.14 (4), p.315-323 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Springer Nature - Complete Springer Journals; Alma/SFX Local Collection |
| subjects | Accumulation Arteriosclerosis - chemically induced Arteriosclerosis - metabolism Arteriosclerosis - physiopathology Base Sequence Biomedical and Life Sciences Cell Biology Cell Line Cholesterol Cholesterol Esters - metabolism Cholesterol, LDL - metabolism Cholesterol, LDL - pharmacology Dexamethasone - pharmacology Enzyme Inhibitors - pharmacology Esters Foam Cells - drug effects Foam Cells - physiology Gene Expression Regulation - drug effects Glucocorticoids - pharmacology Humans Lesions Life Sciences Macrophages - drug effects Macrophages - physiology Molecular Sequence Data Promoter Regions, Genetic - drug effects Receptors, Glucocorticoid - drug effects Receptors, Glucocorticoid - metabolism Response Elements - drug effects RNA, Messenger - drug effects RNA, Messenger - metabolism Sterol O-Acyltransferase - drug effects Sterol O-Acyltransferase - genetics Sterol O-Acyltransferase - metabolism Up-Regulation - drug effects |
| title | Enhancement of human ACAT1 gene expression to promote the macrophage-derived foam cell formation by dexamethasone |
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