Gene-selective modulation by a synthetic oxysterol ligand of the liver X receptor
Gene-selective modulation by a synthetic oxysterol ligand of the liver X receptor
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DOI：
10.1194/jlr.m400257-jlr200
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发表时间：
2004-10-01
影响因子：
6.5
通讯作者：
Nambi, P
中科院分区：
文献类型：
--
作者：
Quinet, EM;Savio, DA;Nambi, P
肝X受体（LXR）通过包括ATP结合盒转运体的上调的机制限制动脉壁损伤部位内的巨噬细胞中的胆固醇积累，在胆固醇稳态的调节中发挥关键作用。这些动脉粥样硬化保护特性使LXR成为心血管疾病药物干预的潜在靶点。然而，它们通过激活固醇反应元件结合蛋白1c（SREBP-1c）表达促进脂肪生成和甘油三酯增加的相关活性代表了潜在的促动脉粥样硬化倾向。新表征的合成氧固醇，N，N-二甲基-3 β-羟基胆烯酰胺（DMHCA），代表了一种基因选择性LXR调节剂，其介导ABCA 1基因表达的有效转录激活，同时在体外和小鼠体内对SREBP-1c表现出最小的影响。DMHCA有可能通过上调肝脏、小肠和腹腔巨噬细胞中的LXR靶基因（包括ABCA 1）来刺激胆固醇转运。然而，与已知的非甾体LXR激动剂相比，DMHCA仅表现出有限的增加肝脏SREBP-1c mRNA的活性，并且不改变循环血浆甘油三酯。基于细胞的研究还表明，DMHCA增强巨噬细胞中的胆固醇流出，并提出了这种选择性调节剂可以潜在地抑制胆固醇积累的机制。DMHCA和LXR的相关基因选择性配体可能在动脉粥样硬化的研究和治疗中具有应用价值。
Liver X receptors (LXRs) play key roles in the regulation of cholesterol homeostasis by limiting cholesterol accumulation in macrophages within arterial wall lesion sites by a mechanism that includes the upregulation of ATP binding cassette transporters. These atheroprotective properties distinguish LXRs as potential targets for pharmaceutical intervention in cardiovascular disease. Their associated activity for promoting lipogenesis and triglyceride accretion through the activation of sterol-response element binding protein 1c (SREBP-1c) expression, however, represents a potential proatherogenic liability. A newly characterized synthetic oxysterol, N,N-dimethyl-3beta-hydroxycholen-amide (DMHCA), represents a gene-selective LXR modulator that mediates potent transcriptional activation of ABCA1 gene expression while exhibiting minimal effects on SREBP-1c both in vitro and in vivo in mice. DMHCA has the potential to stimulate cholesterol transport through the upregulation of LXR target genes, including ABCA1, in liver, small intestine, and peritoneal macrophages. Compared with known nonsteroidal LXR agonists, however, DMHCA exhibits only limited activity for increasing hepatic SREBP-1c mRNA and does not alter circulating plasma triglycerides. Cell-based studies also indicate that DMHCA enhances cholesterol efflux in macrophages and suggest a mechanism whereby this selective modulator can potentially inhibit cholesterol accumulation. DMHCA and related gene-selective ligands of LXR may have application to the study and treatment of atherosclerosis.