PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway
PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway
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DOI：
10.1038/83348
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发表时间：
2001-01-01
期刊：
影响因子：
82.9
通讯作者：
Staels, B
中科院分区：
文献类型：
--
作者：
Chinetti, G;Lestavel, S;Staels, B
过氧化物酶体增殖物激活受体（PPAR）是调节脂质和葡萄糖代谢以及细胞分化的核受体。 PPAR-α 和 PPAR-gamma 均在人类巨噬细胞中表达，发挥抗炎作用。 PPAR-γ 的激活可能通过诱导巨噬细胞清道夫受体 CD36 的表达来促进泡沫细胞的形成。这促使我们研究不同 PPAR 激活剂对人类原代巨噬细胞和 THP-1 巨噬细胞的胆固醇代谢和泡沫细胞形成的影响。在这里，我们证明 PPAR-α 和 PPAR-γ 激活剂不会影响乙酰化低密度脂蛋白诱导的人巨噬细胞泡沫细胞的形成。相比之下，PPAR-α和PPAR-γ激活剂诱导编码ABCA1的基因的表达，ABCA1是一种控制apoAI介导的巨噬细胞胆固醇流出的转运蛋白。这些效应可能是由于肝脏-x-受体α的表达增强所致，这是一种氧化甾醇激活的核受体，可诱导ABCA1-启动子转录。此外，PPAR-α和PPAR-γ激活剂可增加apoAI诱导的胆固醇从正常巨噬细胞的流出。相比之下，PPAR-α 或 PPAR-γ 激活不会影响从丹吉尔病患者分离出的巨噬细胞的胆固醇流出，这是由于 ABCA1 的遗传缺陷造成的。在这里，我们通过激活人巨噬细胞中 ABCA1 介导的胆固醇流出，确定了 PPAR-α 和 PPAR-gamma 在胆固醇反向转运途径第一步中的调节作用。
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR-alpha and PPAR-gamma are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-gamma may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36. This prompted us to investigate the influence of different PPAR- activators on cholesterol metabolism and foam-cell formation of human primary and THP-1 macrophages. Here we show that PPAR-alpha and PPAR-gamma activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-alpha and PPAR-gamma activators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages. These effects are likely due to enhanced expression of liver-x-receptor alpha, an oxysterol-activated nuclear receptor which inducer ABCA1- promoter transcription. Moreover, PPAR-alpha and PPAR-gamma activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR-alpha or PPAR-gamma activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease, which is due to a genetic defect in ABCA1. Here we identify a regulatory role for PPAR-alpha and PPAR-gamma in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.