Liver X receptors inhibit human monocyte-derived macrophage foam cell formation by inhibiting fluid-phase pinocytosis of LDL
Liver X receptors inhibit human monocyte-derived macrophage foam cell formation by inhibiting fluid-phase pinocytosis of LDL
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DOI：
10.1194/jlr.m700170-jlr200
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发表时间：
2007-11-01
影响因子：
6.5
通讯作者：
Kruth, Howard S.
中科院分区：
文献类型：
--
作者：
Buono, Chiara;Li, Yifu;Kruth, Howard S.
肝脏X受体（LXRs）是参与控制脂质代谢和炎症的配体激活的转录因子。最近的几项研究表明，LXR促进胆固醇逆向转运，抑制动脉粥样硬化。我们的研究调查了LXR是否影响巨噬细胞摄取LDL的人单核细胞衍生的巨噬细胞。我们以前已经表明，人单核细胞分化成巨噬细胞与巨噬细胞集落刺激因子（M-CSF）组成性采取大量的天然LDL受体无关，液相胞饮。在本文报道的研究中，在存在或不存在LXR激动剂T0901317或22（R）-羟基胆固醇的M-CSF的情况下，人单核细胞分化为巨噬细胞。然后，将巨噬细胞与天然I-125-LDL孵育以测定LDL摄取。T0901317和22（R）-羟基胆固醇分别抑制68 +/- 1%和69 +/-2%的I-125-LDL摄取，并减少巨噬细胞中的胞饮空泡。I-125-BSA摄取（一种液相胞饮的测量）和I-125-LDL摄取相同，T0901317处理对两者摄取的抑制程度相同。T0901317不影响受体介导的乙酰化LDL摄取，表明LXR效应对脂蛋白的液相胞饮作用具有特异性。我们的研究结果表明，LXRs下调巨噬细胞的低密度脂蛋白的胞饮。这些发现揭示了LXR激动剂可能抑制巨噬细胞胆固醇积累和动脉粥样硬化的另一种新机制，即通过抑制巨噬细胞对LDL的摄取。
Liver X receptors ( LXRs) are ligand-activated transcription factors involved in the control of lipid metabolism and inflammation. Several studies have recently shown that LXRs promote reverse cholesterol transport and inhibit atherosclerosis. Our study investigated whether LXRs affect macrophage uptake of LDL by human monocyte-derived macrophages. We have previously shown that human monocytes differentiated into macrophages with macrophage-colony-stimulating factor ( M-CSF) constitutively take up large amounts of native LDL by receptor-independent, fluid-phase pinocytosis. In the research reported here, human monocytes were differentiated to macrophages in the presence of M-CSF with or without the LXR agonists T0901317 or 22(R)-hydroxycholesterol. Then, macrophages were incubated with native I-125-LDL to determine LDL uptake. T0901317 and 22(R)-hydroxycholesterol inhibited I-125-LDL uptake by 68 +/- 1% and 69 +/- 2%, respectively, and decreased pinocytotic vacuoles in the macrophages. I-125-BSA uptake, a measure of fluid-phase pinocytosis, and I-125-LDL uptake were the same, and T0901317 treatment inhibited uptake of both to the same degree. T0901317 did not affect receptor-mediated uptake of acetylated LDL, showing that the LXR effect is specific for fluid-phase pinocytosis of lipoproteins. Our results show that LXRs downregulate macrophage pinocytosis of LDL. The findings reveal an additional new mechanism by which LXR agonists may inhibit macrophage cholesterol accumulation and atherosclerosis, namely, by inhibiting macrophage uptake of LDL.