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 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.
de Vries-van der Weij
Jitske
J
Leiden University Medical Center, Department of Human Genetics, The Netherlands. a.j.de_vries@lumc.nl
de Haan
Willeke
W
Hu
Lihui
L
Kuif
Maarten
M
Oei
H Ling D W
HL
van der Hoorn
José W A
JW
Havekes
Louis M
LM
Princen
Hans M G
HM
Romijn
Johannes A
JA
Smit
Johannes W A
JW
Rensen
Patrick C N
PC
D000818:Animals; D016588:Anticarcinogenic Agents / Q000009:adverse effects / Q000494:pharmacology; D053318:Apolipoprotein E3 / Q000235:genetics; D000077610:Bexarotene; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004353:Drug Evaluation, Preclinical; D050171:Dyslipidemias / Q000139:chemically induced* / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013764:Tetrahydronaphthalenes / Q000009:adverse effects* / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D016588:Anticarcinogenic Agents; D053318:Apolipoprotein E3; D053480:Cholesterol Ester Transfer Proteins; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D013764:Tetrahydronaphthalenes; D014280:Triglycerides; D000077610:Bexarotene