Cholesterol Transport in Lysosomes

Abstract

C ellular cholesterol trafficking includes numerous individual processes, as cholesterol cannot only be obtained endogenously or exogenously, but also has many possible fates within the cell, including incorporation into membranes, metabolic conversion to a number of diflFerent products, covalent modification of specific proteins, regulation of gene expression, and efflux from the cell. Distinct trafficking pathways are thought to exist for de novo synthesized cholesterol and cholesterol obtained via the receptor-mediated endocyto-sis of low density lipoproteins. Exogenously obtained cholesterol must pass through the endosomal/lysosomal compartment prior to its trafficking to other subcellular sites, such as the endoplasmic reticulum, the Golgi apparatus, and the plasma membrane. The inherited disor-der Niemann-Pick type C, in which abnormal cholesterol trafficking from the endo-lysosomal compartment leads to substantial cholesterol and glycolipid accumulatioin in lysosomes, is caused by defects in either of two genes that encode for proteins designated as NPCl and NPC2. NPCl is a multiple membrane spanning domain protein containing a sterol sensing domain similar to those found in several proteins involved in cholesterol homeostasis. NPC2 is a small intralysosomal protein that has been characterized biochemically as a cholesterol bind-ing and transport protein. While there is abundant evidence suggesting a role for the NPC proteins in late endosomal/lysosomal trafficking of cholesterol, their precise functions and mecha-nisms of action remain to be discovered.