Intracellular cholesterol trafficking: role of the NPC1 protein

Knowledge of intracellular cholesterol transport has been forthcoming from studies of inherited metabolic diseases. Research on Niemann-Pick C disease, characterized by cellular accumulation of lipoprotein derived cholesterol focused first on the intracellular location of the sterol with the presumption that the sites of sterol accumulation in mutant cells relative to normal cells would illuminate pathways of intracellular cholesterol transport. Indeed, the Golgi was highlighted by these studies as playing a pivotal role in cholesterol trafficking. Also, using a morphological approach, pools of cholesterol were discovered within endoplasmic reticulum membranes in cells in which cholesterol esterification had been blocked by inhibition of ACAT. This finding provides support for the speculation that local pools of endoplasmic reticulum membrane cholesterol interact with sterol sensing domains of resident ER proteins regulating cellular cholesterol homeostasis. Recent discoveries of gene encoding protein regulating intracellular cholesterol levels open the way for cellular and molecular biological approaches that should rapidly advance our understanding of defective cholesterol metabolism. Future research promises to reveal unifying principles that underlie intracellular cholesterol trafficking processes. The fundamental knowledge gained will lead to strategies for alleviating defects in cholesterol metabolism. Presently, the genetic and cell biology tools provided by recent findings fuel an exciting time in cholesterol research. Knowledge of the protein products of gene discoveries allows us to probe pathways of cholesterol trafficking in living cells. Only a few of the intracellular locations of 'sterol sensing proteins' are known. Much of the dynamic movement of these proteins as the interact with cellular cholesterol to direct sterol transport remains to be discovered.