Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXRα
Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXRα
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DOI：
10.1073/pnas.200367697
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发表时间：
2000-10-24
影响因子：
11.1
通讯作者：
Tontonoz, P
中科院分区：
文献类型：
--
作者：
Venkateswaran, A;Laffitte, BA;Tontonoz, P
LXRα是一种核受体，此前已被证明可以调节胆固醇向胆汁酸的代谢转化。在这里，我们定义了这个转录因子在控制细胞胆固醇外流中的作用，我们证明了在NIH 3T3成纤维细胞或RAW264.7巨噬细胞中逆转录病毒表达LXRα和/或用LXR的氧固醇配体处理这些细胞时，编码可能的胆固醇/磷脂转运体ATP结合盒(ABC)A1的mRNA诱导了7到30倍，相反，在缺乏AF2转录激活结构域的显性阴性形式的LXRα或LXRβ表达的细胞中，对氧固酮的ABCA1mRNA的诱导被减弱。我们进一步证明了LXRα在NIH3T3成纤维细胞中的表达和/或用氧化甾醇处理这些细胞足以刺激胆固醇外流到细胞外载脂蛋白A1。在带有ABCA1基因功能突变的丹吉尔成纤维细胞中，LXR的氧固醇配体刺激外排的能力显著降低。综上所述，这些结果表明，细胞胆固醇的流入至少在一定程度上是由核受体信号通路在转录水平上控制的。他们提出了一种模型，在该模型中，氧固醇对细胞内固醇负荷的反应激活了LXRs，导致了ABCA1转运蛋白的诱导，并刺激了脂质外流到细胞外受体。这些发现对我们理解哺乳动物的胆固醇动态平衡有重要的意义，并为药物调节细胞脂代谢提供了新的机会。
LXR alpha is a nuclear receptor that has previously been shown to regulate the metabolic conversion of cholesterol to bile acids. Here we define a role for this transcription factor in the control of cellular cholesterol efflux, We demonstrate that retroviral expression of LXR alpha in NIH 3T3 fibroblasts or RAW264.7 macrophages and/or treatment of these cells with oxysterol ligands of LXR results in 7- to 30-fold induction of the mRNA encoding the putative cholesterol/phospholipid transporter ATP-binding cassette (ABC)A1, In contrast, induction of ABCA1 mRNA in response to oxysterols is attenuated in cells that constitutively express dominant-negative forms of LXR alpha or LXR beta that lack the AF2 transcriptional activation domain. We further demonstrate that expression of LXR alpha in NIH 3T3 fibroblasts and/or treatment of these cells with oxysterols is sufficient to stimulate cholesterol efflux to extracellular apolipoprotein A1. The ability of oxysterol ligands of LXR to stimulate efflux is dramatically reduced in Tangier fibroblasts, which carry a loss of function mutation in the ABCA1 gene. Taken together, these results indicate that cellular cholesterol afflux is controlled, at least in part, at the level of transcription by a nuclear receptor-signaling pathway. They suggest a model in which activation of LXRs by oxysterols in response to cellular sterol loading leads to induction of the ABCA1 transporter and the stimulation of lipid efflux to extracellular accepters. These findings have important implications for our understanding of mammalian cholesterol homeostasis and suggest new opportunities for pharmacological regulation of cellular lipid metabolism.