title: Rexinoid bexarotene modulates triglyceride but not cholesterol metabolism via gene-specific permissivity of the RXR/LXR heterodimer in the liver.
abstract: 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.
authors: University Lille Nord de France, Lille, France.
authors: Fanny
authors: F
authors: Lalloyer
authors: Thomas Askov
authors: TA
authors: Pedersen
authors: Barbara
authors: B
authors: Gross
authors: Sophie
authors: S
authors: Lestavel
authors: Saïd
authors: S
authors: Yous
authors: Emmanuelle
authors: E
authors: Vallez
authors: Jan-Ake
authors: JA
authors: Gustafsson
authors: Susanne
authors: S
authors: Mandrup
authors: Catherine
authors: C
authors: Fiévet
authors: Bart
authors: B
authors: Staels
authors: Anne
authors: A
authors: Tailleux
mesh_terms: 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*
chemical_list: 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