D-threo-1-Phenyl-2-decanoylamino-3-morpholino-1-propanol Alters Cellular Cholesterol Homeostasis by Modulating the Endosome Lipid Domains

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• 作者：Asami Makino ; Kumiko Ishii ; Motohide Murate ; Tomohiro Hayakawa ; Yusuke Suzuki ; Minoru Suzuki ; Kazuki Ito ; Tetsuro Fujisawa ; Hirotami Matsuo ; Reiko Ishitsuka ; and Toshihide Kobayashi
• 刊名：Biochemistry
• 出版年：2006
• 出版时间：April 11, 2006
• 年：2006
• 卷：45
• 期：14
• 页码：4530 - 4541
• 全文大小：5969K
• 年卷期：v.45,no.14(April 11, 2006)
• ISSN：1520-4995

文摘

D-threo-1-Phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) is a frequently usedinhibitor of glycosphingolipid biosynthesis. However, some interesting characteristics of D-PDMP cannotbe explained by the inhibition of glycolipid synthesis alone. In the present study, we showed that D-PDMPinhibits the activation of lysosomal acid lipase by late endosome/lysosome specific lipid, bis(monoacylglycero)phosphate (also called as lysobisphosphatidic acid), through alteration of membranestructure of the lipid. When added to cultured fibroblasts, D-PDMP inhibits the degradation of low-densitylipoprotein (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 thedecrease of cell surface cholesterol. We showed that D-PDMP alters cellular cholesterol homeostasis ina glycosphingolipid-independent manner using L-PDMP, a stereoisomer of D-PDMP, which does not inhibitglycosphingolipid synthesis, and mutant melanoma cell which is defective in glycolipid synthesis. Alteringcholesterol homeostasis by D-PDMP explains the unique characteristics of sensitizing multidrug resistantcells by this drug.