Pluronic L81 enhances triacylglycerol accumulation in the cytosol and inhibits chylomicron secretion
Pluronic L81 enhances triacylglycerol accumulation in the cytosol and inhibits chylomicron secretion
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DOI：
10.1194/jlr.m600211-jlr200
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发表时间：
2006-11-01
影响因子：
6.5
通讯作者：
Hussain, M. Mahmood
中科院分区：
文献类型：
--
作者：
Fatma, Sumbul;Yakubov, Reuven;Hussain, M. Mahmood
Pluronic L 81（PL 81）抑制脂肪吸收，其他Pluronic共聚物有助于克服癌细胞的耐药性。为了理解PL 81如何起作用，我们合成了放射性标记的类似物[C-14] PL 81，并基于1H NMR和质谱分析表明其结构与PL 81相似。[C-14] PL 81通过与PL 81类似的分化的Caco-2细胞抑制乳糜微粒（CM）（脂肪吸收所必需的脂蛋白）的分泌。此外，PL 81与[C-14] PL 81的细胞摄取竞争。因此，[C-14] PL 81和PL 81在这些生理测定中表现相似。Caco-2细胞对[C-14] PL 81的摄取具有浓度、时间和温度依赖性，主要发生在顶侧。在细胞内，它被同化在胞质溶胶中。细胞通过对维拉帕米部分敏感的途径向顶侧分泌PL 81。少量分泌到基底外侧与CM无关，这种分泌不受CM组装抑制的影响。然而，PL 81显著抑制作为CM的一部分的三酰基甘油（TG）和磷脂的分泌。PL 81处理的细胞表现出微粒体甘油三酯转移蛋白的活性降低，并积累了更多的TG，但不是磷脂，在他们的胞质溶胶。我们建议，普朗尼克共聚物的行为，干扰出口的分子从胞质溶胶。它们通过减少TG向内质网的转运来抑制脂肪吸收，并通过竞争它们的排泄来增加对癌细胞的药物功效。
Pluronic L81 (PL81) inhibits fat absorption, and other Pluronic copolymers help overcome drug resistance in cancer cells. To understand how PL81 acts, we synthesized a radiolabeled analog, [C-14] PL81, and showed that it was structurally similar to PL81 based on 1 H NMR as well as mass spectrometric analysis. [C-14] PL81 inhibited the secretion of chylomicrons (CMs), lipoproteins essential for fat absorption, by differentiated Caco-2 cells similar to PL81. Moreover, PL81 competed with the cellular uptake of [C-14] PL81. Thus, [C-14] PL81 and PL81 behave similarly in these physiologic assays. Uptake of [C-14] PL81 by Caco-2 cells was concentration-, time-, and temperature-dependent and occurred mainly from the apical side. Intracellularly, it was assimilated in the cytosol. Cells excreted PL81 toward the apical side via a pathway partially sensitive to verapamil. Small amounts were secreted toward the basolateral side unassociated with CM, and this secretion was unaffected by the inhibition of CM assembly. Nonetheless, PL81 significantly inhibited the secretion of triacylglycerols (TGs) and phospholipids as part of CM. PL81-treated cells showed decreased activity of microsomal triglyceride transfer protein and accumulated more TGs, but not phospholipids, in their cytosol. We propose that Pluronic copolymers act by interfering with the export of molecules from the cytosol. They inhibit fat absorption by decreasing TG transport to the endoplasmic reticulum and increase drug efficacy against cancer cells by competing for their excretion.