RESUMO
OBJECTIVE: Liver X receptors (LXRs) are oxysterol-activated nuclear receptors regulating reverse cholesterol transport, in part by modulating cholesterol efflux from macrophages to apoAI and HDL via the ABCA1 and ABCG1/ABCG4 pathways. Moreover, LXR activation increases intracellular cholesterol trafficking via the induction of NPC1 and NPC2 expression. However, implication of LXRs in the selective uptake of cholesteryl esters from lipoproteins in human macrophages has never been reported. METHODS AND RESULTS: Our results show that (1) selective CE uptake from HDL(3) is highly efficient in human monocyte-derived macrophages; (2) surprisingly, HDL(3)-CE uptake is strongly increased by LXR activation despite antiatherogenic effects of LXRs; (3) HDL(3)-CE uptake increase is not linked to SR-BI expression modulation but it is dependent of proteoglycan interactions; (4) HDL(3)-CE uptake increase is associated with increased expression and secretion of apoE and LPL, two proteins interacting with proteoglycans; (5) HDL(3)-CE uptake increase depends on the integrity of raft domains and is associated with an increased caveolin-1 expression. CONCLUSIONS: Our study identifies a new role for LXRs in the control of cholesterol homeostasis in human macrophages. LXR activation results in enhanced dynamic intracellular cholesterol fluxes through an increased CE uptake from HDL and leads to an increased cholesterol availability to efflux to apoAI and HDL.
Assuntos
Ésteres do Colesterol/metabolismo , Proteínas de Ligação a DNA/metabolismo , Lipoproteínas HDL/metabolismo , Macrófagos/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Apolipoproteína A-I/metabolismo , Aterosclerose/etiologia , Aterosclerose/metabolismo , Transporte Biológico Ativo , Caveolina 1/genética , Caveolina 1/metabolismo , Células Cultivadas , HDL-Colesterol/metabolismo , Proteínas de Ligação a DNA/agonistas , Humanos , Hidrocarbonetos Fluorados/farmacologia , Receptores X do Fígado , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Receptores Nucleares Órfãos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Sulfonamidas/farmacologiaRESUMO
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. METHODS AND 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.
