Bexarotene Induces Dyslipidemia by Increased Very Low-Density Lipoprotein Production and Cholesteryl Ester Transfer Protein-Mediated Reduction of High-Density Lipoprotein
A common dose-limiting side effect of treatment with the retinoid X receptor agonist bexarotene is dyslipidemia. We evaluated the effects of bexarotene on plasma lipid metabolism in patients with metastatic differentiated thyroid carcinoma and investigated the underlying mechanism(s) in apolipoprote...
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| Veröffentlicht in: | Endocrinology (Philadelphia) 2009-05, Vol.150 (5), p.2368-2375 |
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| creator | de Vries-van der Weij, Jitske de Haan, Willeke Hu, Lihui Kuif, Maarten Oei, H. Ling D. W van der Hoorn, José W. A Havekes, Louis M Princen, Hans M. G Romijn, Johannes A Smit, Johannes W. A Rensen, Patrick C. N |
| description | A common dose-limiting side effect of treatment with the retinoid X receptor agonist bexarotene is dyslipidemia. We evaluated the effects of bexarotene on plasma lipid metabolism in patients with metastatic differentiated thyroid carcinoma and investigated the underlying mechanism(s) in apolipoprotein (APO) E*3-Leiden mice without (E3L) and with human cholesteryl ester transfer protein (CETP; E3L.CETP). To this end, 10 patients with metastatic differentiated thyroid carcinoma were treated with bexarotene (300 mg/d) for 6 wk. Bexarotene increased plasma triglyceride (TG; +150%), primarily associated with very low-density lipoprotein (VLDL), and raised plasma total cholesterol (+50%). However, whereas bexarotene increased VLDL-cholesterol (C) and low-density lipoprotein (LDL)-C (+63%), it decreased high-density lipoprotein (HDL)-C (−30%) and tended to decrease apoAI (−18%) concomitant with an increase in endogenous CETP activity (+44%). To evaluate the cause of the bexarotene-induced hypertriglyceridemia and the role of CETP in the bexarotene-induced shift in cholesterol distribution, E3L and E3L.CETP mice were treated with bexarotene through dietary supplementation [0.03% (wt/wt)]. Bexarotene increased VLDL-associated TG in both E3L (+47%) and E3L.CETP (+29%) mice by increasing VLDL-TG production (+68%). Bexarotene did not affect the total cholesterol levels or distribution in E3L mice but increased VLDL-C (+11%) and decreased HDL-C (−56%) as well as apoAI (−31%) in E3L.CETP mice, concomitant with increased endogenous CETP activity (+41%). This increased CETP activity by bexarotene-treatment is likely due to the increase in VLDL-TG, a CETP substrate that drives CETP activity. In conclusion, bexarotene causes combined dyslipidemia as reflected by increased TG, VLDL-C, and LDL-C and decreased HDL-C, which is the result of an increased VLDL-TG production that causes an increase of the endogenous CETP activity.
Bexarotene causes hypertriglyceridemia by increasing the VLDL-TG production rate, and increases VLDL-C and decreases HDL-C through increasing the CETP-dependent transfer of cholesterol from HDL to VLDL, as a consequence of an increased VLDL-TG pool. |
| doi_str_mv | 10.1210/en.2008-1540 |
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Bexarotene causes hypertriglyceridemia by increasing the VLDL-TG production rate, and increases VLDL-C and decreases HDL-C through increasing the CETP-dependent transfer of cholesterol from HDL to VLDL, as a consequence of an increased VLDL-TG pool.</description><identifier>ISSN: 0013-7227</identifier><identifier>EISSN: 1945-7170</identifier><identifier>DOI: 10.1210/en.2008-1540</identifier><identifier>PMID: 19147676</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>Animals ; Anticarcinogenic Agents - adverse effects ; Anticarcinogenic Agents - pharmacology ; Apolipoprotein E3 - genetics ; Apolipoproteins ; Cholesterol ; Cholesterol Ester Transfer Proteins - genetics ; Cholesterol Ester Transfer Proteins - metabolism ; Cholesterol Ester Transfer Proteins - physiology ; Cholesteryl ester transfer protein ; Dietary supplements ; Drug Evaluation, Preclinical ; Dyslipidemia ; Dyslipidemias - chemically induced ; Dyslipidemias - metabolism ; High density ; High density lipoprotein ; Humans ; Hypertriglyceridemia ; Lipid metabolism ; Lipids ; Lipoproteins ; Lipoproteins (very low density) ; Lipoproteins, HDL - metabolism ; Lipoproteins, VLDL - metabolism ; Low density lipoprotein ; Male ; Metabolic disorders ; Metastases ; Metastasis ; Mice ; Mice, Transgenic ; Protein turnover ; Proteins ; Receptor density ; Tetrahydronaphthalenes - adverse effects ; Tetrahydronaphthalenes - pharmacology ; Thyroid ; Thyroid cancer ; Thyroid carcinoma ; Triglycerides ; Triglycerides - blood ; Triglycerides - metabolism</subject><ispartof>Endocrinology (Philadelphia), 2009-05, Vol.150 (5), p.2368-2375</ispartof><rights>Copyright © 2009 by The Endocrine Society 2009</rights><rights>Copyright © 2009 by The Endocrine Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c497t-e3b29f8fa42842a7ec756997fdf5aa877018b844f431596eb39a69844a54b4793</citedby><cites>FETCH-LOGICAL-c497t-e3b29f8fa42842a7ec756997fdf5aa877018b844f431596eb39a69844a54b4793</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19147676$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>de Vries-van der Weij, Jitske</creatorcontrib><creatorcontrib>de Haan, Willeke</creatorcontrib><creatorcontrib>Hu, Lihui</creatorcontrib><creatorcontrib>Kuif, Maarten</creatorcontrib><creatorcontrib>Oei, H. Ling D. W</creatorcontrib><creatorcontrib>van der Hoorn, José W. A</creatorcontrib><creatorcontrib>Havekes, Louis M</creatorcontrib><creatorcontrib>Princen, Hans M. G</creatorcontrib><creatorcontrib>Romijn, Johannes A</creatorcontrib><creatorcontrib>Smit, Johannes W. A</creatorcontrib><creatorcontrib>Rensen, Patrick C. N</creatorcontrib><title>Bexarotene Induces Dyslipidemia by Increased Very Low-Density Lipoprotein Production and Cholesteryl Ester Transfer Protein-Mediated Reduction of High-Density Lipoprotein</title><title>Endocrinology (Philadelphia)</title><addtitle>Endocrinology</addtitle><description>A common dose-limiting side effect of treatment with the retinoid X receptor agonist bexarotene is dyslipidemia. We evaluated the effects of bexarotene on plasma lipid metabolism in patients with metastatic differentiated thyroid carcinoma and investigated the underlying mechanism(s) in apolipoprotein (APO) E*3-Leiden mice without (E3L) and with human cholesteryl ester transfer protein (CETP; E3L.CETP). To this end, 10 patients with metastatic differentiated thyroid carcinoma were treated with bexarotene (300 mg/d) for 6 wk. Bexarotene increased plasma triglyceride (TG; +150%), primarily associated with very low-density lipoprotein (VLDL), and raised plasma total cholesterol (+50%). However, whereas bexarotene increased VLDL-cholesterol (C) and low-density lipoprotein (LDL)-C (+63%), it decreased high-density lipoprotein (HDL)-C (−30%) and tended to decrease apoAI (−18%) concomitant with an increase in endogenous CETP activity (+44%). To evaluate the cause of the bexarotene-induced hypertriglyceridemia and the role of CETP in the bexarotene-induced shift in cholesterol distribution, E3L and E3L.CETP mice were treated with bexarotene through dietary supplementation [0.03% (wt/wt)]. Bexarotene increased VLDL-associated TG in both E3L (+47%) and E3L.CETP (+29%) mice by increasing VLDL-TG production (+68%). Bexarotene did not affect the total cholesterol levels or distribution in E3L mice but increased VLDL-C (+11%) and decreased HDL-C (−56%) as well as apoAI (−31%) in E3L.CETP mice, concomitant with increased endogenous CETP activity (+41%). This increased CETP activity by bexarotene-treatment is likely due to the increase in VLDL-TG, a CETP substrate that drives CETP activity. In conclusion, bexarotene causes combined dyslipidemia as reflected by increased TG, VLDL-C, and LDL-C and decreased HDL-C, which is the result of an increased VLDL-TG production that causes an increase of the endogenous CETP activity.
Bexarotene causes hypertriglyceridemia by increasing the VLDL-TG production rate, and increases VLDL-C and decreases HDL-C through increasing the CETP-dependent transfer of cholesterol from HDL to VLDL, as a consequence of an increased VLDL-TG pool.</description><subject>Animals</subject><subject>Anticarcinogenic Agents - adverse effects</subject><subject>Anticarcinogenic Agents - pharmacology</subject><subject>Apolipoprotein E3 - genetics</subject><subject>Apolipoproteins</subject><subject>Cholesterol</subject><subject>Cholesterol Ester Transfer Proteins - genetics</subject><subject>Cholesterol Ester Transfer Proteins - metabolism</subject><subject>Cholesterol Ester Transfer Proteins - physiology</subject><subject>Cholesteryl ester transfer protein</subject><subject>Dietary supplements</subject><subject>Drug Evaluation, Preclinical</subject><subject>Dyslipidemia</subject><subject>Dyslipidemias - chemically induced</subject><subject>Dyslipidemias - metabolism</subject><subject>High density</subject><subject>High density lipoprotein</subject><subject>Humans</subject><subject>Hypertriglyceridemia</subject><subject>Lipid metabolism</subject><subject>Lipids</subject><subject>Lipoproteins</subject><subject>Lipoproteins (very low density)</subject><subject>Lipoproteins, HDL - metabolism</subject><subject>Lipoproteins, VLDL - metabolism</subject><subject>Low density lipoprotein</subject><subject>Male</subject><subject>Metabolic disorders</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Protein turnover</subject><subject>Proteins</subject><subject>Receptor density</subject><subject>Tetrahydronaphthalenes - adverse effects</subject><subject>Tetrahydronaphthalenes - pharmacology</subject><subject>Thyroid</subject><subject>Thyroid cancer</subject><subject>Thyroid carcinoma</subject><subject>Triglycerides</subject><subject>Triglycerides - blood</subject><subject>Triglycerides - metabolism</subject><issn>0013-7227</issn><issn>1945-7170</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU9P3DAQxa2qqGy33HquLPXABS927MTxsV3-SouKEHCNnGRcjHbt1E4E-5X6KXGURVzgNOPR770Z6yH0ndEFyxg9BrfIKC0JywX9hGZMiZxIJulnNKOUcSKzTO6jrzE-pqcQgn9B-0wxIQtZzND_3_Csg-_BAb507dBAxCfbuLadbWFjNa63ad4E0BFafA9hi1f-iZyAi7ZPve18N8qtw9fBJ31vvcPatXj54NcQ-6RY49Ox4tugXTSpuZ4U5Apaq_vkewOvSm_whf378N6Cb2jP6HWEg12do7uz09vlBVn9Ob9c_lqRRijZE-B1pkxptMhKkWkJjcwLpaRpTa51KSVlZV0KYQRnuSqg5koXKg10LmohFZ-jn5Nv2vtvSF-oHv0QXFpZccZprmSeyUQdTVQTfIwBTNUFu9FhWzFajcFU4KoxmGoMJuE_dqZDvYH2Dd4lkYDDCfBD95EV2VnxiQTX-iZYB12AGN-ufPeAF_UTqNc</recordid><startdate>20090501</startdate><enddate>20090501</enddate><creator>de Vries-van der Weij, Jitske</creator><creator>de Haan, Willeke</creator><creator>Hu, Lihui</creator><creator>Kuif, Maarten</creator><creator>Oei, H. 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Ling D. W</au><au>van der Hoorn, José W. A</au><au>Havekes, Louis M</au><au>Princen, Hans M. G</au><au>Romijn, Johannes A</au><au>Smit, Johannes W. A</au><au>Rensen, Patrick C. N</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bexarotene Induces Dyslipidemia by Increased Very Low-Density Lipoprotein Production and Cholesteryl Ester Transfer Protein-Mediated Reduction of High-Density Lipoprotein</atitle><jtitle>Endocrinology (Philadelphia)</jtitle><addtitle>Endocrinology</addtitle><date>2009-05-01</date><risdate>2009</risdate><volume>150</volume><issue>5</issue><spage>2368</spage><epage>2375</epage><pages>2368-2375</pages><issn>0013-7227</issn><eissn>1945-7170</eissn><abstract>A common dose-limiting side effect of treatment with the retinoid X receptor agonist bexarotene is dyslipidemia. We evaluated the effects of bexarotene on plasma lipid metabolism in patients with metastatic differentiated thyroid carcinoma and investigated the underlying mechanism(s) in apolipoprotein (APO) E*3-Leiden mice without (E3L) and with human cholesteryl ester transfer protein (CETP; E3L.CETP). To this end, 10 patients with metastatic differentiated thyroid carcinoma were treated with bexarotene (300 mg/d) for 6 wk. Bexarotene increased plasma triglyceride (TG; +150%), primarily associated with very low-density lipoprotein (VLDL), and raised plasma total cholesterol (+50%). However, whereas bexarotene increased VLDL-cholesterol (C) and low-density lipoprotein (LDL)-C (+63%), it decreased high-density lipoprotein (HDL)-C (−30%) and tended to decrease apoAI (−18%) concomitant with an increase in endogenous CETP activity (+44%). To evaluate the cause of the bexarotene-induced hypertriglyceridemia and the role of CETP in the bexarotene-induced shift in cholesterol distribution, E3L and E3L.CETP mice were treated with bexarotene through dietary supplementation [0.03% (wt/wt)]. Bexarotene increased VLDL-associated TG in both E3L (+47%) and E3L.CETP (+29%) mice by increasing VLDL-TG production (+68%). Bexarotene did not affect the total cholesterol levels or distribution in E3L mice but increased VLDL-C (+11%) and decreased HDL-C (−56%) as well as apoAI (−31%) in E3L.CETP mice, concomitant with increased endogenous CETP activity (+41%). This increased CETP activity by bexarotene-treatment is likely due to the increase in VLDL-TG, a CETP substrate that drives CETP activity. In conclusion, bexarotene causes combined dyslipidemia as reflected by increased TG, VLDL-C, and LDL-C and decreased HDL-C, which is the result of an increased VLDL-TG production that causes an increase of the endogenous CETP activity.
Bexarotene causes hypertriglyceridemia by increasing the VLDL-TG production rate, and increases VLDL-C and decreases HDL-C through increasing the CETP-dependent transfer of cholesterol from HDL to VLDL, as a consequence of an increased VLDL-TG pool.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>19147676</pmid><doi>10.1210/en.2008-1540</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Endocrinology (Philadelphia), 2009-05, Vol.150 (5), p.2368-2375 |
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| language | eng |
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| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Animals Anticarcinogenic Agents - adverse effects Anticarcinogenic Agents - pharmacology Apolipoprotein E3 - genetics Apolipoproteins Cholesterol Cholesterol Ester Transfer Proteins - genetics Cholesterol Ester Transfer Proteins - metabolism Cholesterol Ester Transfer Proteins - physiology Cholesteryl ester transfer protein Dietary supplements Drug Evaluation, Preclinical Dyslipidemia Dyslipidemias - chemically induced Dyslipidemias - metabolism High density High density lipoprotein Humans Hypertriglyceridemia Lipid metabolism Lipids Lipoproteins Lipoproteins (very low density) Lipoproteins, HDL - metabolism Lipoproteins, VLDL - metabolism Low density lipoprotein Male Metabolic disorders Metastases Metastasis Mice Mice, Transgenic Protein turnover Proteins Receptor density Tetrahydronaphthalenes - adverse effects Tetrahydronaphthalenes - pharmacology Thyroid Thyroid cancer Thyroid carcinoma Triglycerides Triglycerides - blood Triglycerides - metabolism |
| title | Bexarotene Induces Dyslipidemia by Increased Very Low-Density Lipoprotein Production and Cholesteryl Ester Transfer Protein-Mediated Reduction of High-Density Lipoprotein |
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