Rexinoid bexarotene modulates triglyceride but not cholesterol metabolism via gene-specific permissivity of the RXR/LXR heterodimer in the liver.
OBJECTIVE
Bexarotene (Targretin) is a clinically used antitumoral agent which exerts its action through binding to and activation of the retinoid-X-receptor (RXR). The most frequent side-effect of bexarotene administration is an increase in plasma triglycerides, an independent risk factor of cardiovascular disease. The molecular mechanism behind this hypertriglyceridemia remains poorly understood.


RESULTS
Using wild-type and LXR alpha/beta-deficient mice, we show here that bexarotene induces hypertriglyceridemia and activates hepatic LXR-target genes of lipogenesis in an LXR-dependent manner, hence exerting a permissive effect on RXR/LXR heterodimers. Interestingly, RNA analysis and Chromatin Immunoprecipitation assays performed in the liver reveal that the in vivo permissive effect of bexarotene on the RXR/LXR heterodimer is restricted to lipogenic genes without modulation of genes controlling cholesterol homeostasis.


CONCLUSIONS
These findings demonstrate that the hypertriglyceridemic action of bexarotene occurs via the RXR/LXR heterodimer and show that RXR heterodimers can act with a selective permissivity on target genes of specific metabolic pathways in the liver.
Lalloyer
Fanny
F
University Lille Nord de France, Lille, France.
Pedersen
Thomas Askov
TA
Gross
Barbara
B
Lestavel
Sophie
S
Yous
Saïd
S
Vallez
Emmanuelle
E
Gustafsson
Jan-Ake
JA
Mandrup
Susanne
S
Fiévet
Catherine
C
Staels
Bart
B
Tailleux
Anne
A
D000818:Animals; D000077610:Bexarotene; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D019281:Dimerization; D005260:Female; D006706:Homeostasis; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000502:physiology*; D047488:Retinoid X Receptors / Q000737:chemistry / Q000502:physiology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism*
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014280:Triglycerides; D002784:Cholesterol; D000077610:Bexarotene