The role of NPC1 regulating the response of the SCAP/SREBP pathway to lipoprotein derived cholesterol

Mammalian cells in vivo generate the majority of their cholesterol by lysosomal hydrolysis of low density lipoprotein (LDL)-derived cholesteryl esters. Free cholesterol produced by this pathway is exported from lysosomes by an unknown process that requires the protein NPC1. Whereas the major pool of cholesterol resides at the plasma membrane, excess cholesterol is transported to the endoplasmic reticulum (ER) where it can be re- esterified to be stored in cytoplasmic lipid droplets. In addition to being removed by esterification, excess cholesterol levels lead to transcriptional suppression of proteins required for cholesterol supply. In order to suppress transcription, cholesterol must reach a complex of regulatory proteins, termed SCAP and SREBP that reside at the interface between ER and Golgi. This proposal aims at investigating the role of NPC1 in LDL- mediated transcriptional regulation by the SCAP/SREBP pathway. Release of lipids from the lysosome is an essential step in normal cell function. A blockage of this process leads to the dramatic phenotype observed in individuals carrying a mutation in NPC 1. To understand the function of NPC1 it is essential to learn more about its subcellular localization. The second aim of this study addresses the question of NPC1 localization.