The RXR agonists PA024 and HX630 have different abilities to activate LXR/RXR and to induce ABCA1 expression in macrophage cell lines
The RXR agonists PA024 and HX630 have different abilities to activate LXR/RXR and to induce ABCA1 expression in macrophage cell lines
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DOI：
10.1016/j.bcp.2008.08.005
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发表时间：
2008-10-15
影响因子：
5.8
通讯作者：
Sawada, Jun-ichi
中科院分区：
文献类型：
--
作者：
Nishimaki-Mogami, Tomoko;Tamehiro, Norimasa;Sawada, Jun-ichi
ATP结合盒转运蛋白（ABC）A1和载脂蛋白释放细胞胆固醇是血浆高密度脂蛋白（HDL）的主要来源。ABC转运蛋白A1（ABCA 1）的表达直接受到肝脏X受体（LXR）/类维生素A X受体（RXR）激活的刺激。我们评估了两种RXR激动剂PA 024和HX 630增加ABCA 1表达的能力。在分化的THP-1细胞中，两种激动剂有效地增强ABCA 1 mRNA表达和apoA-I依赖的细胞胆固醇释放。然而，在RAW 264细胞和未分化的THP-1细胞中，PA 024是高度有效的，而HX 630在增加ABCA 1 mRNA方面是无活性的。平行地，两种激动剂具有不同的以LXR-反应元件（LXRE）-依赖性方式激活ABCA 1启动子和直接刺激LXR α/RXR反式激活的能力。HX 630增强ABCA 1表达的能力与细胞内PPAR γ mRNA水平密切相关。此外，HX 630能够激活PPARgamma/RXR。在RAW 264细胞中转染PPAR γ可诱导HX 630介导的LXRE依赖性转录和ABCA 1启动子的激活，表明HX 630具有激活PPAR γ-LXR-ABCA 1通路的能力。我们的结论是，RXR激动剂PA 024和HX 630具有不同的激活LXR/RXR的能力，并且HX 630对ABCA 1表达和HDL生成的细胞类型依赖性作用与这种缺陷密切相关。(C)2008年爱思唯尔公司All rights reserved.
Release of cellular cholesterol by ATP-binding cassette transporter (ABC)A1 and apolipo-proteins is a major source of plasma high-density lipoprotein (HDL). Expression of ABC transporter A1 (ABCA1) is directly stimulated by liver X receptor (LXR)/retinoid X receptor (RXR) activation. We evaluated the abilities of two RXR agonists, PA024 and HX630, to increase ABCA1 expression. In differentiated THP-1 cells, the two agonists efficiently enhanced ABCA1 mRNA expression and apoA-I-dependent cellular cholesterol release. However, in RAW264 cells and undifferentiated THP-1 cells, PA024 was highly effective while HX630 was inactive in increasing ABCA1 mRNA. In parallel, the two agonists had different abilities to activate ABCA1 promoter in an LXR-responsive-element (LXRE)-dependent manner and to directly stimulate LXR alpha/RXR transactivation. The ability of HX630 to enhance ABCA1 expression was correlated closely with the cellular PPAR gamma mRNA level. Moreover, HX630 was able to activate PPAR gamma/RXR. Transfection of PPAR gamma in RAW264 cells induced HX630-mediated activation of LXRE-dependent transcription and ABCA1 promoter, suggesting the ability of HX630 to activate PPAR gamma-LXR-ABCA1 pathway. We conclude that RXR agonist PA024 and HX630 have different abilities to activate LXR/RXR, and that the cell-type-dependent effect of HX630 on ABCA1 expression and HDL generation is closely associated with this defect. (C) 2008 Elsevier Inc. All rights reserved.