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Bexarotene Induces Dyslipidemia by Increased Very Low-Density Lipoprotein Production and Cholesteryl Ester Transfer Protein-Mediated Reduction of High-Density Lipoprotein

Departments of Human Genetics (J.d.V.-v.d.W.), General Internal Medicine, Endocrinology, and Metabolic Diseases (W.d.H., L.H., M.K., H.L.D.W.O., L.M.H., J.A.R., J.W.A.S., P.C.N.R.), and Cardiology (J.W.A.v.d.H., L.M.H.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; and Gaubius Laboratory (J.d.V.-v.d.W., J.W.A.v.d.H., L.M.H., H.M.G.P.), The Netherlands Organization for Applied Scientific Research-BioSciences, 2301 CE Leiden, The Netherlands

Address all correspondence and requests for reprints to: Jitske de Vries-van der Weij, Leiden University Medical Center, Department of Endocrinology and Metabolic Diseases, C4-R, Albinusdreef 2, 2333 ZA, The Netherlands. E-mail: a.j.de_vries{at}lumc.nl.

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.