Regulation of Sphingomyelin Phosphodiesterase Acid-Like 3A Gene (SMPDL3A) by Liver X Receptors
Regulation of Sphingomyelin Phosphodiesterase Acid-Like 3A Gene (SMPDL3A) by Liver X Receptors
复制标题
DOI：
10.1124/mol.112.078865
复制
发表时间：
2012-10-01
影响因子：
3.6
通讯作者：
Lala, Deepak S.
中科院分区：
文献类型：
--
作者：
Noto, Paul B.;Bukhtiyarov, Yuri;Lala, Deepak S.
肝X受体(LXR) α和LXR β作为胆固醇代谢产物（氧甾醇）的生理传感器，调节参与胆固醇和脂质代谢的关键基因。LXRs已经在人类和啮齿动物细胞系统中进行了广泛的研究，揭示了它们在动脉粥样硬化和炎症性疾病中的潜在治疗价值。LXR基因组图谱已在小鼠巨噬细胞中进行了研究，但尚未在人类THP-1细胞中进行研究，THP-1细胞是研究免疫应答的常用单核/巨噬细胞系统之一。我们使用全基因组筛选方法检测了两种广泛使用的LXR配体[N-（2,2,2-三氟乙基）-N-[4-[2,2,2-三氟-1-羟基-1-（三氟甲基）-乙基]苯基]-苯磺酰胺（T0901317）和3-[3-[N-（2-氯-3-三氟甲基苄基）-（2,2-二苯乙基）氨基]丙氧基]苯乙酸盐盐（GW3965）]处理的THP-1细胞中的直接LXR靶基因。该筛选鉴定鞘磷脂二酯酶样3A （SMPDL3A）基因是一个新的LXR调控基因，其启动子内具有LXR应答元件。我们研究了LXRs在几种人和小鼠细胞类型中对SMPDL3A基因表达的调控。这些研究表明SMPDL3A的诱导是lxr依赖性的，并且仅限于人血细胞，在小鼠细胞系统中未观察到诱导。
Liver X receptor (LXR) alpha and LXR beta function as physiological sensors of cholesterol metabolites (oxysterols), regulating key genes involved in cholesterol and lipid metabolism. LXRs have been extensively studied in both human and rodent cell systems, revealing their potential therapeutic value in the contexts of atherosclerosis and inflammatory diseases. The LXR genome landscape has been investigated in murine macrophages but not in human THP-1 cells, which represent one of the frequently used monocyte/macrophage cell systems to study immune responses. We used a whole-genome screen to detect direct LXR target genes in THP-1 cells treated with two widely used LXR ligands [N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)-ethyl]phenyl]-benzenesulfonamide (T0901317) and 3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino] propyloxy] phenylacetic acid hydrochloride (GW3965)]. This screen identified the sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) gene as a novel LXR-regulated gene, with an LXR response element within its promoter. We investigated the regulation of SMPDL3A gene expression by LXRs across several human and mouse cell types. These studies indicate that the induction of SMPDL3A is LXR-dependent and is restricted to human blood cells with no induction observed in mouse cellular systems.