Asunto(s)
Arteriosclerosis , Homeostasis , Metabolismo de los Lípidos , Receptores Citoplasmáticos y Nucleares/fisiología , Factores de Transcripción/fisiología , Vasculitis , Animales , Regulación de la Expresión Génica , Humanos , Mediadores de Inflamación , Receptores Citoplasmáticos y Nucleares/análisis , Receptores Citoplasmáticos y Nucleares/genética , Distribución Tisular , Factores de Transcripción/análisis , Factores de Transcripción/genéticaRESUMEN
By using BAC transgenic mice, we have shown that increased human ABCA1 protein expression results in a significant increase in cholesterol efflux in different tissues and marked elevation in high density lipoprotein (HDL)-cholesterol levels associated with increases in apoAI and apoAII. Three novel ABCA1 transcripts containing three different transcription initiation sites that utilize sequences in intron 1 have been identified. In BAC transgenic mice there is an increased expression of ABCA1 protein, but the distribution of the ABCA1 product in different cells remains similar to wild type mice. An internal promoter in human intron 1 containing liver X response elements is functional in vivo and directly contributes to regulation of the human ABCA1 gene in multiple tissues and to raised HDL cholesterol, apoAI, and apoAII levels. A highly significant relationship between raised protein levels, increased efflux, and level of HDL elevation is evident. These data provide proof of the principle that increased human ABCA1 efflux activity is associated with an increase in HDL levels in vivo.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/fisiología , Apolipoproteína A-I/metabolismo , HDL-Colesterol/metabolismo , Ratones Transgénicos , Regiones Promotoras Genéticas , Receptores Citoplasmáticos y Nucleares , Receptores de Ácido Retinoico/genética , Receptores de Hormona Tiroidea/genética , Elementos de Respuesta , Transportador 1 de Casete de Unión a ATP , Animales , Secuencia de Bases , Células COS , Línea Celular , Células Cultivadas , Colesterol/metabolismo , Clonación Molecular , Proteínas de Unión al ADN , Humanos , Inmunohistoquímica , Intrones , Lípidos/sangre , Hígado/metabolismo , Receptores X del Hígado , Macrófagos/metabolismo , Ratones , Modelos Genéticos , Datos de Secuencia Molecular , Receptores Nucleares Huérfanos , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Activación Transcripcional , Transfección , Células Tumorales CultivadasRESUMEN
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR-alpha and PPAR-gamma are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-alpha may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36. This prompted us to investigate the influence of different PPAR-activators on cholesterol metabolism and foam-cell formation of human primary and THP-1 macrophages. Here we show that PPAR-alpha and PPAR-gamma activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-alpha and PPAR-gamma activators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages. These effects are likely due to enhanced expression of liver-x-receptor alpha, an oxysterol-activated nuclear receptor which induces ABCA1-promoter transcription. Moreover, PPAR-alpha and PPAR-gamma activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR-alpha or PPAR-gamma activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease, which is due to a genetic defect in ABCA1. Here we identify a regulatory role for PPAR-alpha and PPAR-gamma in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.