RESUMEN
Liver X receptors (LXRs) regulate the expression of genes involved in cholesterol and fatty acid homeostasis, including the genes for ATP-binding cassette transporter A1 (ABCA1) and sterol response element binding protein 1 (SREBP1). Loss of LXR leads to derepression of the ABCA1 gene in macrophages and the intestine, while the SREBP1c gene remains transcriptionally silent. Here we report that high-density-lipoprotein (HDL) cholesterol levels are increased in LXR-deficient mice, suggesting that derepression of ABCA1 and possibly other LXR target genes in selected tissues is sufficient to result in enhanced HDL biogenesis at the whole-body level. We provide several independent lines of evidence indicating that the repressive actions of LXRs are dependent on interactions with the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptors (SMRT). While dissociation of NCoR and SMRT results in derepression of the ABCA1 gene in macrophages, it is not sufficient for derepression of the SREBP1c gene. These findings reveal differential requirements for corepressors in the regulation of genes involved in cholesterol and fatty acid homeostasis and raise the possibility that these interactions may be exploited to develop synthetic ligands that selectively modulate LXR actions in vivo.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica , Regiones Promotoras Genéticas , Receptores Citoplasmáticos y Nucleares/fisiología , Factores de Transcripción , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/biosíntesis , Animales , Northern Blotting , Western Blotting , Células de la Médula Ósea/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/biosíntesis , Diferenciación Celular , Línea Celular , Colesterol/metabolismo , HDL-Colesterol/metabolismo , Cromatina/metabolismo , Proteínas de Unión al ADN/biosíntesis , Silenciador del Gen , Genotipo , Ligandos , Receptores X del Hígado , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Proteínas Nucleares , Co-Represor 1 de Receptor Nuclear , Receptores Nucleares Huérfanos , Pruebas de Precipitina , ARN/metabolismo , Proteínas Represoras , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Hormonas Tiroideas/metabolismo , Transcripción Genética , Transfección , Regulación hacia ArribaRESUMEN
Recent studies have identified the liver X receptors (LXRalpha and LXRbeta) as important regulators of cholesterol and lipid metabolism. Although originally identified as liver-enriched transcription factors, LXRs are also expressed in skeletal muscle, a tissue that accounts for approximately 40% of human total body weight and is the major site of glucose utilization and fatty acid oxidation. Nevertheless, no studies have yet addressed the functional role of LXRs in muscle. In this work we utilize a combination of in vivo and in vitro analysis to demonstrate that LXRs can functionally regulate genes involved in cholesterol metabolism in skeletal muscle. Furthermore we show that treatment of muscle cells in vitro with synthetic agonists of LXR increases the efflux of intracellular cholesterol to extracellular acceptors such as high density lipoprotein, thus identifying this tissue as a potential important regulator of reverse cholesterol transport and high density lipoprotein levels. Additionally we demonstrate that LXRalpha and a subset of LXR target genes are induced during myogenesis, suggesting a role for LXR-dependent signaling in the differentiation process.
Asunto(s)
Colesterol/metabolismo , Homeostasis/fisiología , Metabolismo de los Lípidos , Músculo Esquelético/metabolismo , Receptores Citoplasmáticos y Nucleares/fisiología , Receptores de Ácido Retinoico/fisiología , Receptores de Hormona Tiroidea/fisiología , Animales , Transporte Biológico , Línea Celular , Proteínas de Unión al ADN , Receptores X del Hígado , Ratones , Ratones Noqueados , Músculo Esquelético/citología , Receptores Nucleares Huérfanos , Receptores Citoplasmáticos y Nucleares/genética , Receptores de Ácido Retinoico/genética , Receptores de Hormona Tiroidea/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Recent studies have identified the liver X receptors (LXR alpha and LXR beta) as important regulators of cholesterol metabolism and transport. LXRs control transcription of genes critical to a range of biological functions including regulation of high density lipoprotein cholesterol metabolism, hepatic cholesterol catabolism, and intestinal sterol absorption. Although LXR activity has been proposed to be critical for physiologic lipid metabolism and transport, direct evidence linking LXR signaling pathways to the pathogenesis of cardiovascular disease has yet to be established. In this study bone marrow transplantations were used to selectively eliminate macrophage LXR expression in the context of murine models of atherosclerosis. Our results demonstrate that LXRs are endogenous inhibitors of atherogenesis. Additionally, elimination of LXR activity in bone marrow-derived cells mimics many aspects of Tangier disease, a human high density lipoprotein deficiency, including aberrant regulation of cholesterol transporter expression, lipid accumulation in macrophages, splenomegaly, and increased atherosclerosis. These results identify LXRs as targets for intervention in cardiovascular disease.