D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol alters cellular cholesterol homeostasis by modulating the endosome lipid domains
D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol alters cellular cholesterol homeostasis by modulating the endosome lipid domains
复制标题
DOI：
10.1021/bi052104y
复制
发表时间：
2006-04-11
期刊：
影响因子：
2.9
通讯作者：
Kobayashi, T
中科院分区：
文献类型：
--
作者：
Makino, A;Ishii, K;Kobayashi, T
D-苏型-1-苯基-2-癸酰氨基-3-吗啉基-1-丙醇（D-PdR）是一种常用的鞘糖脂生物合成抑制剂。然而，一些有趣的特性的D-磷脂不能解释的抑制糖脂合成单独。在本研究中，我们表明，D-磷脂酰胆碱抑制激活溶酶体酸性脂肪酶的晚期内体/溶酶体特异性脂质，双-（单酰基甘油）磷酸（也称为lysobisphosphatidic酸），通过改变膜结构的脂质。当添加到培养的成纤维细胞中时，D-脯氨酸抑制低密度脂蛋白（LDL）的降解，从而在晚期内体/溶酶体中积累胆固醇酯和游离胆固醇。这种积累导致LDL衍生的胆固醇酯化的抑制和细胞表面胆固醇的减少。我们发现，D-多巴以非鞘糖脂依赖的方式改变细胞胆固醇稳态，使用L-多巴，D-多巴的立体异构体，它不抑制鞘糖脂合成，和突变的黑色素瘤细胞，这是糖脂合成缺陷。D-多巴改变胆固醇稳态解释了这种药物致敏多药耐药细胞的独特特征。
D-threo-1-Phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) is a frequently used inhibitor of glycosphingolipid biosynthesis. However, some interesting; characteristics Of D-PDMP cannot be explained by the inhibition of glycolipid synthesis alone. In the present study, we showed that D-PDMP inhibits the activation of lysosomal acid lipase by late endosome/lysosome specific lipid, bis-(monoacylglycero)phosphate (also called as lysobisphosphatidic acid), through alteration of membrane structure of the lipid. When added to cultured fibroblasts, D-PDMP inhibits the degradation of low-density lipoprotein (LDL) and thus accumulates both cholesterol ester and free cholesterol in late endosomes/lysosomes. This accumulation results in the inhibition of LDL-derived cholesterol esterification and the decrease of cell surface cholesterol. We showed that D-PDMP alters cellular cholesterol homeostasis in a glycosphingolipid-independent manner using L-PDMP, a stereoisomer Of D-PDMP, which does not inhibit glycosphingolipid synthesis, and mutant melanoma cell which is defective in glycolipid synthesis. Altering cholesterol homeostasis by D-PDMP explains the unique characteristics of sensitizing multidrug resistant cells by this drug.