The dynamin chemical inhibitor dynasore impairs cholesterol trafficking and sterol-sensitive genes transcription in human HeLa cells and macrophages.
The dynamin chemical inhibitor dynasore impairs cholesterol trafficking and sterol-sensitive genes transcription in human HeLa cells and macrophages.
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DOI：
10.1371/journal.pone.0029042
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Védie B
中科院分区：
文献类型：
--
作者：
Girard E;Paul JL;Fournier N;Beaune P;Johannes L;Lamaze C;Védie B
细胞内胆固醇转运有助于调节细胞内胆固醇稳态的机制尚不明确。在这项研究中，我们描述了dynasore的影响，这是一种最近描述的药物，可以特异性抑制dynamin的酶活性，dynamin是一种调节受体内吞作用和胆固醇运输的GTPase。Dynasore强烈抑制HeLa细胞对低密度脂蛋白（LDL）的摄取，并在人巨噬细胞中有较低程度的抑制作用。在这两种细胞类型中，王朝处理导致内溶酶体网络内LDL和游离胆固醇（FC）的异常积累。胆固醇酯（CE）的测定进一步表明，调节胆固醇向内质网（ER）的传递不足。这导致三个主要的甾醇敏感基因，即甾醇调节元件结合蛋白2 （SREBP-2）、3-羟基-3-甲基辅酶还原酶（HMGCoAR）和低密度脂蛋白受体（LDLR）的转录控制受到抑制。胆固醇在内溶酶体腔室的隔离损害了HMDM的主动和被动胆固醇外排。我们的数据进一步说明了膜运输在胆固醇稳态中的重要性，并验证了dynasore作为研究胆固醇细胞内运输的新药理学工具。
Intracellular transport of cholesterol contributes to the regulation of cellular cholesterol homeostasis by mechanisms that are yet poorly defined. In this study, we characterized the impact of dynasore, a recently described drug that specifically inhibits the enzymatic activity of dynamin, a GTPase regulating receptor endocytosis and cholesterol trafficking. Dynasore strongly inhibited the uptake of low-density lipoprotein (LDL) in HeLa cells, and to a lower extent in human macrophages. In both cell types, dynasore treatment led to the abnormal accumulation of LDL and free cholesterol (FC) within the endolysosomal network. The measure of cholesterol esters (CE) further showed that the delivery of regulatory cholesterol to the endoplasmic reticulum (ER) was deficient. This resulted in the inhibition of the transcriptional control of the three major sterol-sensitive genes, sterol-regulatory element binding protein 2 (SREBP-2), 3-hydroxy-3-methyl-coenzymeA reductase (HMGCoAR), and low-density lipoprotein receptor (LDLR). The sequestration of cholesterol in the endolysosomal compartment impaired both the active and passive cholesterol efflux in HMDM. Our data further illustrate the importance of membrane trafficking in cholesterol homeostasis and validate dynasore as a new pharmacological tool to study the intracellular transport of cholesterol.
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