Figure 1.

Mechanisms that protect cells from excess accumulation of FC. Lipoprotein-derived cholesterol is distributed to peripheral cellular sites from a putative FC-sorting organelle, which may be a type of late endosome. The npc1 protein is depicted in this organelle as one of the molecules that are known to influence cholesterol trafficking. The cholesterol trafficking itineraries depicted here include transport to ACAT in the endoplasmic reticulum, leading to cholesterol esterification, and to sites of cholesterol efflux in the plasma membrane, leading to removal of cholesterol if appropriate extracellular cholesterol acceptors are present. Not depicted here are those pathways that downregulate the LDL receptor and cholesterol biosynthetic enzymes and those pathways in specialized cells that lead to the metabolism of cholesterol to other molecules, like bile acids and steroid hormones. As described in the text, FC accumulation can occur via inhibition of cholesterol transport to ACAT or to the plasma membrane, or by direct inhibition of ACAT or cholesterol efflux molecules. An increase in neutral cholesteryl esterase (NCEH) activity in the absence of compensatory re-esterification or efflux of cholesterol could also lead to FC accumulation.