Fate of endogenously synthesized cholesterol in Niemann-Pick type C1 cells
Fate of endogenously synthesized cholesterol in Niemann-Pick type C1 cells
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DOI：
10.1074/jbc.m008272200
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发表时间：
2000-12-29
影响因子：
4.8
通讯作者：
Chang, TY
中科院分区：
文献类型：
--
作者：
Cruz, JC;Chang, TY
哺乳动物细胞通过两条途径获得胆固醇：内质网中的内源性合成和主要通过低密度脂蛋白（LDL）受体途径的外源性来源。我们进行了脉冲追踪实验，以监测内源性合成的胆固醇的命运，并表明，从内质网到达质膜后，新合成的胆固醇最终积累在尼曼-匹克型C1（NPC 1）细胞的内部隔室。因此，NPC 1细胞中内源性合成的胆固醇的最终命运与LDL衍生的胆固醇相同。然而，内源性胆固醇在体内积累所需的时间比LDL衍生的胆固醇慢得多。因此，不同的途径管理后质膜运输的内源性胆固醇和LDL衍生的胆固醇的内部隔室，使用抑制剂N-丁基脱氧野尻霉素，它耗尽细胞复合物鞘糖脂的结果表明，在NPC 1细胞中的胆固醇运输缺陷不是由神经节苷脂积累。NPC疾病死亡的最终原因是中枢神经系统的进行性神经功能恶化，其中胆固醇的主要来源来自内源性合成。我们目前的研究提供了内源性胆固醇细胞内运输缺陷与C型尼曼-匹克病病因之间的合理联系。
Mammalian cells obtain cholesterol via two pathways: endogenous synthesis in the endoplasmic reticulum and exogenous sources mainly through the low density lipoprotein (LDL) receptor pathway. We performed pulse-chase experiments to monitor the fate of endogenously synthesized cholesterol and showed that, after reaching the plasma membrane from the endoplasmic reticulum, the newly synthesized cholesterol eventually accumulates in an internal compartment in Niemann-Pick type C1 (NPC1) cells. Thus, the ultimate fate of endogenously synthesized cholesterol in NPC1 cells is the same as LDL-derived cholesterol. However, the time required for endogenous cholesterol to accumulate internally is much slower than LDL-derived cholesterol. Different pathways thus govern the post-plasma membrane trafficking of endogenous cholesterol and LDL-derived cholesterol to the internal compartment, Results using the inhibitor N-butyldeoxynojirimycin, which depletes cellular complex glycosphingolipids, demonstrates that the cholesterol trafficking defect in NPC1 cells is not caused by ganglioside accumulation. The ultimate cause of death in NPC disease is progressive neurological deterioration in the central nervous system, where the major source of cholesterol is derived from endogenous synthesis. Our current study provides a plausible link between defects in intracellular trafficking of endogenous cholesterol and the etiology of Niemann-Pick type C disease.