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Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages
Removal of cholesterol from macrophage-derived foam cells is a critical step to the prevention of atherosclerotic lesions. We have recently demonstrated the functional importance of retinoids in the regulation of the steroidogenic acute regulatory (StAR) protein that predominantly mediates the intra...
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| Published in: | Biochemical and biophysical research communications 2015-08, Vol.464 (1), p.312-317 |
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| container_title | Biochemical and biophysical research communications |
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| creator | Manna, Pulak R. Sennoune, Souad R. Martinez-Zaguilan, Raul Slominski, Andrzej T. Pruitt, Kevin |
| description | Removal of cholesterol from macrophage-derived foam cells is a critical step to the prevention of atherosclerotic lesions. We have recently demonstrated the functional importance of retinoids in the regulation of the steroidogenic acute regulatory (StAR) protein that predominantly mediates the intramitochondrial transport of cholesterol in target tissues. In the present study, treatment of mouse macrophages with retinoids, particularly all-trans retinoic acid (atRA) and 9-cis RA, resulted in increases in cholesterol efflux to apolipoprotein AI (Apo-A1). Activation of the PKA pathway by a cAMP analog, (Bu)2cAMP, markedly augmented retinoid mediated cholesterol efflux. Macrophages overexpressing hormone-sensitive lipase increased the hydrolysis of cholesteryl esters and concomitantly enhanced the efficacy of retinoic acid receptor and liver X receptor (LXR) ligands on StAR and ATP-binding cassette transporter A1 (ABCA1) protein levels. RAs elevated StAR promoter activity in macrophages, and an increase in StAR levels augmented cholesterol efflux to Apo-A1, suggesting retinoid-mediated efflux of cholesterol involves enhanced oxysterol production. Further studies revealed that retinoids activate the LXR regulated genes, sterol receptor-element binding protein-1c and ABCA1. These findings provide insights into the regulatory events in which retinoid signaling effectively enhances macrophage cholesterol efflux and indicate that retinoid therapy may have important implications in limiting and/or regressing atherosclerotic cardiovascular disease.
•Retinoids effectively enhance cholesterol efflux in mouse macrophages.•Control of StAR mediated oxysterol production is influenced by retinoids.•Retinoid mediated regulation of cholesterol efflux involves the LXR regulatory pathway.•Retinoid signaling may have implications in limiting/regressing atherosclerotic lesions. |
| doi_str_mv | 10.1016/j.bbrc.2015.06.150 |
| format | article |
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•Retinoids effectively enhance cholesterol efflux in mouse macrophages.•Control of StAR mediated oxysterol production is influenced by retinoids.•Retinoid mediated regulation of cholesterol efflux involves the LXR regulatory pathway.•Retinoid signaling may have implications in limiting/regressing atherosclerotic lesions.</description><identifier>ISSN: 0006-291X</identifier><identifier>EISSN: 1090-2104</identifier><identifier>DOI: 10.1016/j.bbrc.2015.06.150</identifier><identifier>PMID: 26119689</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>ABCA1 ; Animals ; Apolipoprotein A-I - metabolism ; ATP Binding Cassette Transporter 1 - genetics ; ATP Binding Cassette Transporter 1 - metabolism ; Biological Transport - drug effects ; Bucladesine - pharmacology ; Cell Line ; Cholesterol - metabolism ; Cholesterol efflux ; Cholesterol Esters - metabolism ; Cyclic AMP-Dependent Protein Kinases - genetics ; Cyclic AMP-Dependent Protein Kinases - metabolism ; Gene Expression Regulation ; HSL ; Hydrolysis - drug effects ; Liver X Receptors ; LXR ; Macrophages ; Macrophages - cytology ; Macrophages - drug effects ; Macrophages - metabolism ; Mice ; Mitochondria - drug effects ; Mitochondria - metabolism ; Orphan Nuclear Receptors - agonists ; Orphan Nuclear Receptors - genetics ; Orphan Nuclear Receptors - metabolism ; Phosphoproteins - genetics ; Phosphoproteins - metabolism ; Receptors, Retinoic Acid - genetics ; Receptors, Retinoic Acid - metabolism ; Retinoids ; Signal Transduction ; StAR ; Sterol Esterase - genetics ; Sterol Esterase - metabolism ; Tretinoin - analogs & derivatives ; Tretinoin - pharmacology</subject><ispartof>Biochemical and biophysical research communications, 2015-08, Vol.464 (1), p.312-317</ispartof><rights>2015 Elsevier Inc.</rights><rights>Copyright © 2015 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c426t-54956394ea58b4ca7d9990f4808673a1303f5b3fbc87d3bff1627cc371a545733</citedby><cites>FETCH-LOGICAL-c426t-54956394ea58b4ca7d9990f4808673a1303f5b3fbc87d3bff1627cc371a545733</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26119689$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Manna, Pulak R.</creatorcontrib><creatorcontrib>Sennoune, Souad R.</creatorcontrib><creatorcontrib>Martinez-Zaguilan, Raul</creatorcontrib><creatorcontrib>Slominski, Andrzej T.</creatorcontrib><creatorcontrib>Pruitt, Kevin</creatorcontrib><title>Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages</title><title>Biochemical and biophysical research communications</title><addtitle>Biochem Biophys Res Commun</addtitle><description>Removal of cholesterol from macrophage-derived foam cells is a critical step to the prevention of atherosclerotic lesions. We have recently demonstrated the functional importance of retinoids in the regulation of the steroidogenic acute regulatory (StAR) protein that predominantly mediates the intramitochondrial transport of cholesterol in target tissues. In the present study, treatment of mouse macrophages with retinoids, particularly all-trans retinoic acid (atRA) and 9-cis RA, resulted in increases in cholesterol efflux to apolipoprotein AI (Apo-A1). Activation of the PKA pathway by a cAMP analog, (Bu)2cAMP, markedly augmented retinoid mediated cholesterol efflux. Macrophages overexpressing hormone-sensitive lipase increased the hydrolysis of cholesteryl esters and concomitantly enhanced the efficacy of retinoic acid receptor and liver X receptor (LXR) ligands on StAR and ATP-binding cassette transporter A1 (ABCA1) protein levels. RAs elevated StAR promoter activity in macrophages, and an increase in StAR levels augmented cholesterol efflux to Apo-A1, suggesting retinoid-mediated efflux of cholesterol involves enhanced oxysterol production. Further studies revealed that retinoids activate the LXR regulated genes, sterol receptor-element binding protein-1c and ABCA1. These findings provide insights into the regulatory events in which retinoid signaling effectively enhances macrophage cholesterol efflux and indicate that retinoid therapy may have important implications in limiting and/or regressing atherosclerotic cardiovascular disease.
•Retinoids effectively enhance cholesterol efflux in mouse macrophages.•Control of StAR mediated oxysterol production is influenced by retinoids.•Retinoid mediated regulation of cholesterol efflux involves the LXR regulatory pathway.•Retinoid signaling may have implications in limiting/regressing atherosclerotic lesions.</description><subject>ABCA1</subject><subject>Animals</subject><subject>Apolipoprotein A-I - metabolism</subject><subject>ATP Binding Cassette Transporter 1 - genetics</subject><subject>ATP Binding Cassette Transporter 1 - metabolism</subject><subject>Biological Transport - drug effects</subject><subject>Bucladesine - pharmacology</subject><subject>Cell Line</subject><subject>Cholesterol - metabolism</subject><subject>Cholesterol efflux</subject><subject>Cholesterol Esters - metabolism</subject><subject>Cyclic AMP-Dependent Protein Kinases - genetics</subject><subject>Cyclic AMP-Dependent Protein Kinases - metabolism</subject><subject>Gene Expression Regulation</subject><subject>HSL</subject><subject>Hydrolysis - drug effects</subject><subject>Liver X Receptors</subject><subject>LXR</subject><subject>Macrophages</subject><subject>Macrophages - cytology</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - metabolism</subject><subject>Mice</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Orphan Nuclear Receptors - agonists</subject><subject>Orphan Nuclear Receptors - genetics</subject><subject>Orphan Nuclear Receptors - metabolism</subject><subject>Phosphoproteins - genetics</subject><subject>Phosphoproteins - metabolism</subject><subject>Receptors, Retinoic Acid - genetics</subject><subject>Receptors, Retinoic Acid - metabolism</subject><subject>Retinoids</subject><subject>Signal Transduction</subject><subject>StAR</subject><subject>Sterol Esterase - genetics</subject><subject>Sterol Esterase - metabolism</subject><subject>Tretinoin - analogs & derivatives</subject><subject>Tretinoin - pharmacology</subject><issn>0006-291X</issn><issn>1090-2104</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><recordid>eNp9kMFq3DAURUVpaSZJf6CLomU3dp8sS7agmxLSNhAIlAayE7L8lGiQralkm_Tvq2HSLrt6m3sP9x1C3jOoGTD5aV8PQ7J1A0zUIGsm4BXZMVBQNQza12QHALJqFHs4I-c57wEYa6V6S84ayZiSvdqR8AMf12AWH2caHU24-Dn6kU44erPgSO1TDJgXTDFQdC6sz9TPWwwbZhr8hok-lJbFwxITNXbx2wnmZzrFNSOdjE3x8GQeMV-SN86EjO9e7gW5_3r98-p7dXv37ebqy21l20YulWiVkFy1aEQ_tNZ0o1IKXNtDLztuGAfuxMDdYPtu5INzTDadtbxjRrSi4_yCfDxxDyn-Wst6PflsMQQzY9mkmVQ9cGiZKNHmFC0jc07o9CH5yaTfmoE-WtZ7fbSsj5Y1SF0sl9KHF_46FFH_Kn-1lsDnUwDLl5vHpLP1ONsitbha9Bj9__h_APe8j3U</recordid><startdate>20150814</startdate><enddate>20150814</enddate><creator>Manna, Pulak R.</creator><creator>Sennoune, Souad R.</creator><creator>Martinez-Zaguilan, Raul</creator><creator>Slominski, Andrzej T.</creator><creator>Pruitt, Kevin</creator><general>Elsevier Inc</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>7X8</scope></search><sort><creationdate>20150814</creationdate><title>Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages</title><author>Manna, Pulak R. ; Sennoune, Souad R. ; Martinez-Zaguilan, Raul ; Slominski, Andrzej T. ; Pruitt, Kevin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c426t-54956394ea58b4ca7d9990f4808673a1303f5b3fbc87d3bff1627cc371a545733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>ABCA1</topic><topic>Animals</topic><topic>Apolipoprotein A-I - metabolism</topic><topic>ATP Binding Cassette Transporter 1 - genetics</topic><topic>ATP Binding Cassette Transporter 1 - metabolism</topic><topic>Biological Transport - drug effects</topic><topic>Bucladesine - pharmacology</topic><topic>Cell Line</topic><topic>Cholesterol - metabolism</topic><topic>Cholesterol efflux</topic><topic>Cholesterol Esters - metabolism</topic><topic>Cyclic AMP-Dependent Protein Kinases - genetics</topic><topic>Cyclic AMP-Dependent Protein Kinases - metabolism</topic><topic>Gene Expression Regulation</topic><topic>HSL</topic><topic>Hydrolysis - drug effects</topic><topic>Liver X Receptors</topic><topic>LXR</topic><topic>Macrophages</topic><topic>Macrophages - cytology</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - metabolism</topic><topic>Mice</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - metabolism</topic><topic>Orphan Nuclear Receptors - agonists</topic><topic>Orphan Nuclear Receptors - genetics</topic><topic>Orphan Nuclear Receptors - metabolism</topic><topic>Phosphoproteins - genetics</topic><topic>Phosphoproteins - metabolism</topic><topic>Receptors, Retinoic Acid - genetics</topic><topic>Receptors, Retinoic Acid - metabolism</topic><topic>Retinoids</topic><topic>Signal Transduction</topic><topic>StAR</topic><topic>Sterol Esterase - genetics</topic><topic>Sterol Esterase - metabolism</topic><topic>Tretinoin - analogs & derivatives</topic><topic>Tretinoin - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Manna, Pulak R.</creatorcontrib><creatorcontrib>Sennoune, Souad R.</creatorcontrib><creatorcontrib>Martinez-Zaguilan, Raul</creatorcontrib><creatorcontrib>Slominski, Andrzej T.</creatorcontrib><creatorcontrib>Pruitt, Kevin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Biochemical and biophysical research communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Manna, Pulak R.</au><au>Sennoune, Souad R.</au><au>Martinez-Zaguilan, Raul</au><au>Slominski, Andrzej T.</au><au>Pruitt, Kevin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages</atitle><jtitle>Biochemical and biophysical research communications</jtitle><addtitle>Biochem Biophys Res Commun</addtitle><date>2015-08-14</date><risdate>2015</risdate><volume>464</volume><issue>1</issue><spage>312</spage><epage>317</epage><pages>312-317</pages><issn>0006-291X</issn><eissn>1090-2104</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Removal of cholesterol from macrophage-derived foam cells is a critical step to the prevention of atherosclerotic lesions. We have recently demonstrated the functional importance of retinoids in the regulation of the steroidogenic acute regulatory (StAR) protein that predominantly mediates the intramitochondrial transport of cholesterol in target tissues. In the present study, treatment of mouse macrophages with retinoids, particularly all-trans retinoic acid (atRA) and 9-cis RA, resulted in increases in cholesterol efflux to apolipoprotein AI (Apo-A1). Activation of the PKA pathway by a cAMP analog, (Bu)2cAMP, markedly augmented retinoid mediated cholesterol efflux. Macrophages overexpressing hormone-sensitive lipase increased the hydrolysis of cholesteryl esters and concomitantly enhanced the efficacy of retinoic acid receptor and liver X receptor (LXR) ligands on StAR and ATP-binding cassette transporter A1 (ABCA1) protein levels. RAs elevated StAR promoter activity in macrophages, and an increase in StAR levels augmented cholesterol efflux to Apo-A1, suggesting retinoid-mediated efflux of cholesterol involves enhanced oxysterol production. Further studies revealed that retinoids activate the LXR regulated genes, sterol receptor-element binding protein-1c and ABCA1. These findings provide insights into the regulatory events in which retinoid signaling effectively enhances macrophage cholesterol efflux and indicate that retinoid therapy may have important implications in limiting and/or regressing atherosclerotic cardiovascular disease.
•Retinoids effectively enhance cholesterol efflux in mouse macrophages.•Control of StAR mediated oxysterol production is influenced by retinoids.•Retinoid mediated regulation of cholesterol efflux involves the LXR regulatory pathway.•Retinoid signaling may have implications in limiting/regressing atherosclerotic lesions.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>26119689</pmid><doi>10.1016/j.bbrc.2015.06.150</doi><tpages>6</tpages></addata></record> |
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| subjects | ABCA1 Animals Apolipoprotein A-I - metabolism ATP Binding Cassette Transporter 1 - genetics ATP Binding Cassette Transporter 1 - metabolism Biological Transport - drug effects Bucladesine - pharmacology Cell Line Cholesterol - metabolism Cholesterol efflux Cholesterol Esters - metabolism Cyclic AMP-Dependent Protein Kinases - genetics Cyclic AMP-Dependent Protein Kinases - metabolism Gene Expression Regulation HSL Hydrolysis - drug effects Liver X Receptors LXR Macrophages Macrophages - cytology Macrophages - drug effects Macrophages - metabolism Mice Mitochondria - drug effects Mitochondria - metabolism Orphan Nuclear Receptors - agonists Orphan Nuclear Receptors - genetics Orphan Nuclear Receptors - metabolism Phosphoproteins - genetics Phosphoproteins - metabolism Receptors, Retinoic Acid - genetics Receptors, Retinoic Acid - metabolism Retinoids Signal Transduction StAR Sterol Esterase - genetics Sterol Esterase - metabolism Tretinoin - analogs & derivatives Tretinoin - pharmacology |
| title | Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages |
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