The RXR agonist bexarotene improves cholesterol homeostasis and inhibits atherosclerosis progression in a mouse model of mixed dyslipidemia.
OBJECTIVE
The activity of the antitumoral agent bexarotene (Targretin, Bexarotene) depends on its binding to the nuclear retinoid-X receptor (RXR) and subsequent transcriptional regulation of target genes. Through RXR activation, bexarotene may modulate numerous metabolic pathways involved in atherosclerosis. Here, we investigated the effect of bexarotene on atherosclerosis progression in a dyslipidemic murine model, the human apolipoprotein E2 knockin mouse, that develops essentially macrophage-laden lesions.


RESULTS
Atherosclerotic lesions together with different metabolic pathways involved in atherosclerosis were investigated in mice treated or not with bexarotene. Bexarotene protects from atherosclerosis development in mice, at least in part by improving the circulating cholesterol distribution profile likely via a marked decrease of dietary cholesterol absorption caused by modulation of intestinal expression of genes recently identified as major players in this process, Niemann-Pick-C1-Like1 (NPC1L1) and CD13. This atheroprotection appears despite a strong hypertriglyceridemia. Moreover, bexarotene treatment only modestly modulates inflammatory gene expression in the vascular wall, but markedly enhanced the capacity of macrophages to efflux cellular lipids.


CONCLUSIONS
These data provide evidence of a favorable pharmacological effect of bexarotene on atherosclerosis despite the induction of hypertriglyceridemia, likely via a beneficial action on intestinal absorption and macrophage efflux.
Lalloyer
Fanny
F
Institut Pasteur de Lille, Département d'Athérosclérose, Lille, France.
Fiévet
Catherine
C
Lestavel
Sophie
S
Torpier
Gérard
G
van der Veen
Jelske
J
Touche
Véronique
V
Bultel
Stéphanie
S
Yous
Saïd
S
Kuipers
Folkert
F
Paumelle
Réjane
R
Fruchart
Jean-Charles
JC
Staels
Bart
B
Tailleux
Anne
A
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D053329:Apolipoprotein E2 / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D000077610:Bexarotene; D018826:CD13 Antigens / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects* / Q000502:physiology; D007408:Intestinal Absorption / Q000187:drug effects; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D047488:Retinoid X Receptors / Q000819:agonists*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood
C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D053329:Apolipoprotein E2; D008074:Lipoproteins; D026901:Membrane Transport Proteins; C482445:Npc1l1 protein, mouse; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014280:Triglycerides; D002784:Cholesterol; D000077610:Bexarotene; D018826:CD13 Antigens