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Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression
In addition to efficiently decreasing VLDL-triglycerides (TGs), fenofibrate increases HDL-cholesterol levels in humans. We investigated whether the fenofibrate-induced increase in HDL-cholesterol is dependent on the expression of the cholesteryl ester transfer protein (CETP). To this end, APOE*3-Lei...
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Published in: | Journal of lipid research 2007-08, Vol.48 (8), p.1763-1771 |
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creator | van der Hoogt, Caroline C. de Haan, Willeke Westerterp, Marit Hoekstra, Menno Dallinga-Thie, Geesje M. Romijn, Johannes A. Princen, Hans M.G. Jukema, J. Wouter Havekes, Louis M. Rensen, Patrick C.N. |
description | In addition to efficiently decreasing VLDL-triglycerides (TGs), fenofibrate increases HDL-cholesterol levels in humans. We investigated whether the fenofibrate-induced increase in HDL-cholesterol is dependent on the expression of the cholesteryl ester transfer protein (CETP). To this end, APOE*3-Leiden (E3L) transgenic mice without and with the human CETP transgene, under the control of its natural regulatory flanking regions, were fed a Western-type diet with or without fenofibrate. Fenofibrate (0.04% in the diet) decreased plasma TG in E3L and E3L.CETP mice (−59% and −60%; P < 0.001), caused by a strong reduction in VLDL. Whereas fenofibrate did not affect HDL-cholesterol in E3L mice, fenofibrate dose-dependently increased HDL-cholesterol in E3L.CETP mice (up to +91%). Fenofibrate did not affect the turnover of HDL-cholesteryl ester (CE), indicating that fenofibrate causes a higher steady-state HDL-cholesterol level without altering the HDL-cholesterol flux through plasma. Analysis of the hepatic gene expression profile showed that fenofibrate did not differentially affect the main players in HDL metabolism in E3L.CETP mice compared with E3L mice. However, in E3L.CETP mice, fenofibrate reduced hepatic CETP mRNA (−72%; P < 0.01) as well as the CE transfer activity in plasma (−73%; P < 0.01). We conclude that fenofibrate increases HDL-cholesterol by reducing the CETP-dependent transfer of cholesterol from HDL to (V)LDL, as related to lower hepatic CETP expression and a reduced plasma (V)LDL pool. |
doi_str_mv | 10.1194/jlr.M700108-JLR200 |
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Wouter ; Havekes, Louis M. ; Rensen, Patrick C.N.</creator><creatorcontrib>van der Hoogt, Caroline C. ; de Haan, Willeke ; Westerterp, Marit ; Hoekstra, Menno ; Dallinga-Thie, Geesje M. ; Romijn, Johannes A. ; Princen, Hans M.G. ; Jukema, J. Wouter ; Havekes, Louis M. ; Rensen, Patrick C.N.</creatorcontrib><description>In addition to efficiently decreasing VLDL-triglycerides (TGs), fenofibrate increases HDL-cholesterol levels in humans. We investigated whether the fenofibrate-induced increase in HDL-cholesterol is dependent on the expression of the cholesteryl ester transfer protein (CETP). To this end, APOE*3-Leiden (E3L) transgenic mice without and with the human CETP transgene, under the control of its natural regulatory flanking regions, were fed a Western-type diet with or without fenofibrate. Fenofibrate (0.04% in the diet) decreased plasma TG in E3L and E3L.CETP mice (−59% and −60%; P < 0.001), caused by a strong reduction in VLDL. Whereas fenofibrate did not affect HDL-cholesterol in E3L mice, fenofibrate dose-dependently increased HDL-cholesterol in E3L.CETP mice (up to +91%). Fenofibrate did not affect the turnover of HDL-cholesteryl ester (CE), indicating that fenofibrate causes a higher steady-state HDL-cholesterol level without altering the HDL-cholesterol flux through plasma. Analysis of the hepatic gene expression profile showed that fenofibrate did not differentially affect the main players in HDL metabolism in E3L.CETP mice compared with E3L mice. However, in E3L.CETP mice, fenofibrate reduced hepatic CETP mRNA (−72%; P < 0.01) as well as the CE transfer activity in plasma (−73%; P < 0.01). We conclude that fenofibrate increases HDL-cholesterol by reducing the CETP-dependent transfer of cholesterol from HDL to (V)LDL, as related to lower hepatic CETP expression and a reduced plasma (V)LDL pool.</description><identifier>ISSN: 0022-2275</identifier><identifier>EISSN: 1539-7262</identifier><identifier>DOI: 10.1194/jlr.M700108-JLR200</identifier><identifier>PMID: 17525476</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Apolipoproteins B - blood ; Cholesterol Ester Transfer Proteins - genetics ; Cholesterol Ester Transfer Proteins - metabolism ; Cholesterol Esters - blood ; Cholesterol Esters - metabolism ; Cholesterol, HDL - blood ; Fenofibrate - pharmacology ; fibrate ; Gene Expression - drug effects ; high density lipoprotein ; Humans ; Hypolipidemic Agents - pharmacology ; Liver - metabolism ; Male ; Mice ; Mice, Transgenic ; peroxisome proliferator-activated receptor α ; RNA, Messenger - metabolism ; transgenic mice</subject><ispartof>Journal of lipid research, 2007-08, Vol.48 (8), p.1763-1771</ispartof><rights>2007 © 2007 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c580t-d4807261193aec71a51fc3d26f3d97e408aa8008ba3bb34b90d9d8d556d81a873</citedby><cites>FETCH-LOGICAL-c580t-d4807261193aec71a51fc3d26f3d97e408aa8008ba3bb34b90d9d8d556d81a873</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S002222752042512X$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3549,27924,27925,45780</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17525476$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>van der Hoogt, Caroline C.</creatorcontrib><creatorcontrib>de Haan, Willeke</creatorcontrib><creatorcontrib>Westerterp, Marit</creatorcontrib><creatorcontrib>Hoekstra, Menno</creatorcontrib><creatorcontrib>Dallinga-Thie, Geesje M.</creatorcontrib><creatorcontrib>Romijn, Johannes A.</creatorcontrib><creatorcontrib>Princen, Hans M.G.</creatorcontrib><creatorcontrib>Jukema, J. Wouter</creatorcontrib><creatorcontrib>Havekes, Louis M.</creatorcontrib><creatorcontrib>Rensen, Patrick C.N.</creatorcontrib><title>Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression</title><title>Journal of lipid research</title><addtitle>J Lipid Res</addtitle><description>In addition to efficiently decreasing VLDL-triglycerides (TGs), fenofibrate increases HDL-cholesterol levels in humans. We investigated whether the fenofibrate-induced increase in HDL-cholesterol is dependent on the expression of the cholesteryl ester transfer protein (CETP). To this end, APOE*3-Leiden (E3L) transgenic mice without and with the human CETP transgene, under the control of its natural regulatory flanking regions, were fed a Western-type diet with or without fenofibrate. Fenofibrate (0.04% in the diet) decreased plasma TG in E3L and E3L.CETP mice (−59% and −60%; P < 0.001), caused by a strong reduction in VLDL. Whereas fenofibrate did not affect HDL-cholesterol in E3L mice, fenofibrate dose-dependently increased HDL-cholesterol in E3L.CETP mice (up to +91%). Fenofibrate did not affect the turnover of HDL-cholesteryl ester (CE), indicating that fenofibrate causes a higher steady-state HDL-cholesterol level without altering the HDL-cholesterol flux through plasma. Analysis of the hepatic gene expression profile showed that fenofibrate did not differentially affect the main players in HDL metabolism in E3L.CETP mice compared with E3L mice. However, in E3L.CETP mice, fenofibrate reduced hepatic CETP mRNA (−72%; P < 0.01) as well as the CE transfer activity in plasma (−73%; P < 0.01). We conclude that fenofibrate increases HDL-cholesterol by reducing the CETP-dependent transfer of cholesterol from HDL to (V)LDL, as related to lower hepatic CETP expression and a reduced plasma (V)LDL pool.</description><subject>Animals</subject><subject>Apolipoproteins B - blood</subject><subject>Cholesterol Ester Transfer Proteins - genetics</subject><subject>Cholesterol Ester Transfer Proteins - metabolism</subject><subject>Cholesterol Esters - blood</subject><subject>Cholesterol Esters - metabolism</subject><subject>Cholesterol, HDL - blood</subject><subject>Fenofibrate - pharmacology</subject><subject>fibrate</subject><subject>Gene Expression - drug effects</subject><subject>high density lipoprotein</subject><subject>Humans</subject><subject>Hypolipidemic Agents - pharmacology</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>peroxisome proliferator-activated receptor α</subject><subject>RNA, Messenger - metabolism</subject><subject>transgenic mice</subject><issn>0022-2275</issn><issn>1539-7262</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNp9kN1u1DAQhS0EokvLC3ABeYGUsePEtsQNaukP2qoStNeWf8aLV2m8slPEvj1usyp3XM1odM6ZmY-QDxROKVX883bMpzcCgIJsv69_MIBXZEX7TrWCDew1WQEw1jIm-iPyrpRtVXI-0LfkiIqe9VwMK6IvcEoh2mxmbOLkMpqCpbk6X7fuVxqxzJjT2Nh9k9E_ujhtmpf5fmyeazNnM5VQm11OM8apwT-7jKXENJ2QN8GMBd8f6jG5v_h2d3bVrm8vr8--1i29hLn1XEI9ur7VGXSCmp4G13k2hM4rgRykMRJAWtNZ23GrwCsvfd8PXlIjRXdMrpdcn8xW73J8MHmvk4n6eZDyRps8RzeiDkpwRCUUWM-dGywEZiT3SikrDPc1iy1ZLqdSMoaXPAr6ibyu5PWBvF7IV9PHxbR7tA_o_1kOqKvg0yIIJmmzybHo-58MaAcgpOKcVsWXRYEV1O-IWRcXcXLoY0Y310_i_y74C5gAnyY</recordid><startdate>20070801</startdate><enddate>20070801</enddate><creator>van der Hoogt, Caroline C.</creator><creator>de Haan, Willeke</creator><creator>Westerterp, Marit</creator><creator>Hoekstra, Menno</creator><creator>Dallinga-Thie, Geesje M.</creator><creator>Romijn, Johannes A.</creator><creator>Princen, Hans M.G.</creator><creator>Jukema, J. 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Wouter</creatorcontrib><creatorcontrib>Havekes, Louis M.</creatorcontrib><creatorcontrib>Rensen, Patrick C.N.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Directory of Open Access Journals</collection><jtitle>Journal of lipid research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>van der Hoogt, Caroline C.</au><au>de Haan, Willeke</au><au>Westerterp, Marit</au><au>Hoekstra, Menno</au><au>Dallinga-Thie, Geesje M.</au><au>Romijn, Johannes A.</au><au>Princen, Hans M.G.</au><au>Jukema, J. Wouter</au><au>Havekes, Louis M.</au><au>Rensen, Patrick C.N.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression</atitle><jtitle>Journal of lipid research</jtitle><addtitle>J Lipid Res</addtitle><date>2007-08-01</date><risdate>2007</risdate><volume>48</volume><issue>8</issue><spage>1763</spage><epage>1771</epage><pages>1763-1771</pages><issn>0022-2275</issn><eissn>1539-7262</eissn><abstract>In addition to efficiently decreasing VLDL-triglycerides (TGs), fenofibrate increases HDL-cholesterol levels in humans. We investigated whether the fenofibrate-induced increase in HDL-cholesterol is dependent on the expression of the cholesteryl ester transfer protein (CETP). To this end, APOE*3-Leiden (E3L) transgenic mice without and with the human CETP transgene, under the control of its natural regulatory flanking regions, were fed a Western-type diet with or without fenofibrate. Fenofibrate (0.04% in the diet) decreased plasma TG in E3L and E3L.CETP mice (−59% and −60%; P < 0.001), caused by a strong reduction in VLDL. Whereas fenofibrate did not affect HDL-cholesterol in E3L mice, fenofibrate dose-dependently increased HDL-cholesterol in E3L.CETP mice (up to +91%). Fenofibrate did not affect the turnover of HDL-cholesteryl ester (CE), indicating that fenofibrate causes a higher steady-state HDL-cholesterol level without altering the HDL-cholesterol flux through plasma. Analysis of the hepatic gene expression profile showed that fenofibrate did not differentially affect the main players in HDL metabolism in E3L.CETP mice compared with E3L mice. However, in E3L.CETP mice, fenofibrate reduced hepatic CETP mRNA (−72%; P < 0.01) as well as the CE transfer activity in plasma (−73%; P < 0.01). We conclude that fenofibrate increases HDL-cholesterol by reducing the CETP-dependent transfer of cholesterol from HDL to (V)LDL, as related to lower hepatic CETP expression and a reduced plasma (V)LDL pool.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>17525476</pmid><doi>10.1194/jlr.M700108-JLR200</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Apolipoproteins B - blood Cholesterol Ester Transfer Proteins - genetics Cholesterol Ester Transfer Proteins - metabolism Cholesterol Esters - blood Cholesterol Esters - metabolism Cholesterol, HDL - blood Fenofibrate - pharmacology fibrate Gene Expression - drug effects high density lipoprotein Humans Hypolipidemic Agents - pharmacology Liver - metabolism Male Mice Mice, Transgenic peroxisome proliferator-activated receptor α RNA, Messenger - metabolism transgenic mice |
title | Fenofibrate increases HDL-cholesterol by reducing cholesteryl ester transfer protein expression |
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