Bexarotene induces dyslipidemia by increased very low-density lipoprotein production and cholesteryl ester transfer protein-mediated reduction of high-density lipoprotein

Endocrinology. 2009 May;150(5):2368-75. doi: 10.1210/en.2008-1540. Epub 2009 Jan 15.


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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticarcinogenic Agents / adverse effects
  • Anticarcinogenic Agents / pharmacology
  • Apolipoprotein E3 / genetics
  • Bexarotene
  • Cholesterol Ester Transfer Proteins / genetics
  • Cholesterol Ester Transfer Proteins / metabolism
  • Cholesterol Ester Transfer Proteins / physiology*
  • Drug Evaluation, Preclinical
  • Dyslipidemias / chemically induced*
  • Dyslipidemias / metabolism
  • Humans
  • Lipoproteins, HDL / metabolism*
  • Lipoproteins, VLDL / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Tetrahydronaphthalenes / adverse effects*
  • Tetrahydronaphthalenes / pharmacology
  • Triglycerides / blood
  • Triglycerides / metabolism


  • Anticarcinogenic Agents
  • Apolipoprotein E3
  • Cholesterol Ester Transfer Proteins
  • Lipoproteins, HDL
  • Lipoproteins, VLDL
  • Tetrahydronaphthalenes
  • Triglycerides
  • Bexarotene