Bultel Stephanie, Helin Lionel, Clavey Veronique, Chinetti-Gbaguidi Giulia, Rigamonti Elena, Colin Morvane, Fruchart Jean-Charles, Staels Bart, Lestavel Sophie
Institut Pasteur de Lille, Inserm, U545, Université de Lille 2, Faculté de Pharmacie et de Médecine Lille, Lille, France.
Arterioscler Thromb Vasc Biol. 2008 Dec;28(12):2288-95. doi: 10.1161/ATVBAHA.108.175042. Epub 2008 Sep 18.
Liver X receptors (LXRs) are oxysterol-activated nuclear receptors regulating reverse cholesterol transport, in part by modulating cholesterol efflux from macrophages to apoAI and HDL via the ABCA1 and ABCG1/ABCG4 pathways. Moreover, LXR activation increases intracellular cholesterol trafficking via the induction of NPC1 and NPC2 expression. However, implication of LXRs in the selective uptake of cholesteryl esters from lipoproteins in human macrophages has never been reported.
Our results show that (1) selective CE uptake from HDL(3) is highly efficient in human monocyte-derived macrophages; (2) surprisingly, HDL(3)-CE uptake is strongly increased by LXR activation despite antiatherogenic effects of LXRs; (3) HDL(3)-CE uptake increase is not linked to SR-BI expression modulation but it is dependent of proteoglycan interactions; (4) HDL(3)-CE uptake increase is associated with increased expression and secretion of apoE and LPL, two proteins interacting with proteoglycans; (5) HDL(3)-CE uptake increase depends on the integrity of raft domains and is associated with an increased caveolin-1 expression.
Our study identifies a new role for LXRs in the control of cholesterol homeostasis in human macrophages. LXR activation results in enhanced dynamic intracellular cholesterol fluxes through an increased CE uptake from HDL and leads to an increased cholesterol availability to efflux to apoAI and HDL.
肝脏X受体（LXRs）是一种被氧化甾醇激活的核受体，它通过ABCA1和ABCG1/ABCG4途径调节逆向胆固醇转运，部分是通过调节巨噬细胞向载脂蛋白AI和高密度脂蛋白（HDL）的胆固醇流出实现的。此外，LXR激活通过诱导NPC1和NPC2的表达增加细胞内胆固醇转运。然而，LXRs在人类巨噬细胞从脂蛋白中选择性摄取胆固醇酯方面的作用从未被报道过。
我们的结果表明：（1）人类单核细胞衍生的巨噬细胞从HDL（3）中选择性摄取胆固醇酯的效率很高；（2）令人惊讶的是，尽管LXRs具有抗动脉粥样硬化作用，但LXR激活仍能显著增加HDL（3）-胆固醇酯的摄取；（3）HDL（3）-胆固醇酯摄取的增加与SR-BI表达的调节无关，但依赖于蛋白聚糖相互作用；（4）HDL（3）-胆固醇酯摄取的增加与载脂蛋白E和脂蛋白脂肪酶（LPL）的表达和分泌增加有关，这两种蛋白与蛋白聚糖相互作用；（5）HDL（3）-胆固醇酯摄取的增加取决于脂筏结构域的完整性，并与小窝蛋白-1表达的增加有关。
我们的研究确定了LXRs在人类巨噬细胞胆固醇稳态控制中的新作用。LXR激活通过增加从HDL摄取胆固醇酯，导致细胞内胆固醇动态通量增强，并增加了胆固醇向载脂蛋白AI和HDL流出的可用性。
