Fate of endogenously synthesized cholesterol in Niemann-Pick type C1 cells

Mammalian cells obtain cholesterol via two pathways: endogenous synthesis i n the endoplasmic reticulum and exogenous sources mainly through the low de nsity lipoprotein (LDL) receptor pathway. We performed pulse-chase experime nts to monitor the fate of endogenously synthesized cholesterol and showed that, after reaching the plasma membrane from the endoplasmic reticulum, th e newly synthesized cholesterol eventually accumulates in an internal compa rtment in Niemann-Pick type C1 (NPC1) cells. Thus, the ultimate fate of end ogenously synthesized cholesterol in NPC1 cells is the same as LDL-derived cholesterol. However, the time required for endogenous cholesterol to accum ulate internally is much slower than LDL-derived cholesterol. Different pat hways thus govern the post-plasma membrane trafficking of endogenous choles terol and LDL-derived cholesterol to the internal compartment, Results usin g the inhibitor N-butyldeoxynojirimycin, which depletes cellular complex gl ycosphingolipids, demonstrates that the cholesterol trafficking defect in N PC1 cells is not caused by ganglioside accumulation. The ultimate cause of death in NPC disease is progressive neurological deterioration in the centr al nervous system, where the major source of cholesterol is derived from en dogenous synthesis. Our current study provides a plausible link between def ects in intracellular trafficking of endogenous cholesterol and the etiolog y of Niemann-Pick type C disease.