HDL biology
Rising VLDL-triglyceride from bexarotene drives CETP activity up and HDL cholesterol down (Endocrinology 2009)
Original title: Bexarotene induces dyslipidemia by increased very low-density lipoprotein production and cholesteryl ester transfer protein-mediated reduction of high-density lipoprotein
In 10 patients with metastatic differentiated thyroid carcinoma treated with the retinoid X receptor agonist bexarotene (300 mg/d) for six weeks, triglyceride rose 150%, total cholesterol rose 50%, VLDL-C and LDL-C rose 63%, HDL-C fell 30%, apoAI tended to fall 18%, and endogenous CETP activity rose 44%. In APOE*3-Leiden mice with and without human CETP expression, bexarotene raised VLDL-triglyceride via a 68% increase in VLDL-TG production in both strains, but only in CETP-expressing mice did this translate into higher VLDL-cholesterol (+11%), lower HDL-cholesterol (-56%), lower apoAI (-31%), and higher endogenous CETP activity (+41%), showing that bexarotene's rise in VLDL-triglyceride, a CETP substrate, is what drives the increase in CETP activity and consequent HDL lowering.
Original 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.
HDL biologymechanismspharmacology
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.