Ceramide in Lipid Particles Enhances Heparan Sulfate Proteoglycan and Low Density Lipoprotein Receptor-related Protein-mediated Uptake by Macrophages*
Ceramide in Lipid Particles Enhances Heparan Sulfate Proteoglycan and Low Density Lipoprotein Receptor-related Protein-mediated Uptake by Macrophages*
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DOI：
10.1074/jbc.m402035200
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发表时间：
2004-06
影响因子：
4.8
通讯作者：
Shin-ya Morita;Misa Kawabe;Atsushi Sakurai;Keiichiro Okuhira;A. Vertut-Doï;M. Nakano;T. Handa
中科院分区：
文献类型：
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作者：
Shin-ya Morita;Misa Kawabe;Atsushi Sakurai;Keiichiro Okuhira;A. Vertut-Doï;M. Nakano;T. Handa
动脉壁鞘磷脂酶(SMase)被认为与动脉粥样硬化的形成有关。脂蛋白的sMase修饰已被证明发生在动脉粥样硬化病变中，并促进其被巨噬细胞摄取和泡沫细胞的形成。为了探讨SMase促进巨噬细胞摄取的机制，我们制备了以鞘磷脂(SM)或神经酰胺(CER)为模型颗粒的脂乳剂。SMase能显著增加不含载脂蛋白的J774巨噬细胞对含SM乳剂的摄取。SMase处理后乳状液的摄取量与微粒聚集程度呈负相关，而含CER乳状液的摄取量显著大于含SM乳状液，说明乳状液摄取率的提高是由于微粒中CER分子的生成，而不是由于SMase的聚集。硫酸肝素蛋白多糖(HSPGs)和低密度脂蛋白受体相关蛋白(LRP)对CER增强乳状液摄取至关重要，因为肝素或乳铁蛋白抑制乳状液摄取。共聚焦显微镜还显示，SMase促进了J774巨噬细胞对乳剂的结合和内化，这一作用几乎被乳铁蛋白消除。与含SM的乳剂相比，载脂蛋白E进一步增加了含CER乳剂的摄取。这些发现表明，SMase在脂蛋白中产生CER，促进巨噬细胞通过HSPG和LRP途径摄取，在泡沫细胞的形成中发挥关键作用。因此，CER可能是一种重要的致动脉粥样硬化分子。
Arterial wall sphingomyelinase (SMase) has been proposed to be involved in atherogenesis. SMase modification of lipoproteins has been shown to occur in atherosclerotic lesions and to facilitate their uptake by macrophages and foam cell formation. To investigate the mechanism of macrophage uptake enhanced by SMase, we prepared lipid emulsions containing sphingomyelin (SM) or ceramide (CER) as model particles of lipoproteins. SMase remarkably increased the uptake of SM-containing emulsions by J774 macrophages without apolipoproteins. The emulsion uptake was negatively correlated with the degree of particle aggregation by pretreatment with SMase, whereas the uptake of CER-containing emulsions was significantly larger than SM-containing emulsions, indicating that enhancement of uptake is due to the generation of CER molecules in particles but not to the aggregation by SMase. Heparan sulfate proteoglycans (HSPGs) and low density lipoprotein receptor-related protein (LRP) were crucial for CER-enhanced emulsion uptake, because heparin or lactoferrin inhibited the emulsion uptake. Confocal microscopy also showed that SMase promoted both binding and internalization of emulsions by J774 macrophages, which were almost abolished by lactoferrin. Apolipoprotein E further increased the uptake of CER-containing emulsions compared with SM-containing emulsions. These findings suggest the generation of CER in lipoproteins by SMase facilitates the macrophage uptake via HSPG and LRP pathways and plays a crucial role in foam cell formation. Thus, CER may act as an important atherogenic molecule.