Cholesterol is delivered to cells as cholesterol ester in low density lipoproteins. In normal cells, hydrolysis of cholesterol ester in lysosomes frees cholesterol which moves out of lysosomes to other intracellular sites and ultimately becomes incorporated into the cell plasma membrane. Defects in intracellular cholesterol transport pathways result in loss of homeostatic responses that regulate cholesterol synthesis, uptake and esterification. Niemann Pick type C disease (NP-C) is a genetic disorder in which LDL derived cholesterol accumulates intracellularly and does not elicit the homeostatic responses of normal cells. Studies comparing normal and NP-C fibroblasts have helped to define some of the critical steps in intracellular cholesterol transport. In both normal and NP-C cells, endogenously derived LDL cholesterol freed in lysosomes is transported to the Golgi complex. However, only in NP-C cells does cholesterol accumulate in membranes of trans Golgi cisternae apparently detained en route to other cytoplasmic sites. The NP-C phenotype suggests a protein mediates trafficking of lysosomal cholesterol to other cellular membranes. Recent discovery of the NPC1 gene and examination of the NPC1 protein reveals amino acid sequences that have homology with other proteins involved in regulation of levels of intracellular cholesterol. Future studies on the NPC1 protein should provide information on intracellular cholesterol trafficking and the feedback mechanism that controls its cellular levels. Cholesterol ester and triacylglycerol stores in steroidogenic cells and adipocytes are a result of both de novo synthesis and uptake of lipoprotein derived cholesterol and fatty acids. These neutral lipid stores are compartmentalized in the cell within a monolayer leaflet of endoplasmic reticulum. We have located three proteins associated with lipid metabolism, perilipin (HL), hormone sensitive lipase (HSL) and adipocyte differentiation related protein (ADRP), to this monolayer using immunocytochemistry. The association of both PL and HSL with the monolayer surface is affected by hormonal stimulation. Thus, the monolayer leaflet of intracellular lipid storage droplets is not just a surface container separating neutral lipid from the cytosol but an active metabolic site where proteins come and go to effect lipid metabolism.
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