title: Physiological and coordinate downregulation of the NPC1 and NPC2 genes are associated with the sequestration of LDL-derived cholesterol within endocytic compartments.
abstract: The Niemann-Pick C1 and C2 (NPC1 and NPC2) proteins have a central role in regulating the transport of lipoprotein-derived cholesterol from endocytic compartments to the endoplasmic reticulum for esterification by acyl-CoA:cholesterol acyltransferase (ACAT) and feedback inhibition of the sterol regulatory element-binding protein (SREBP) pathway. Since the NPC1 gene/protein has recently been shown to be downregulated by feedback inhibition of the SREBP pathway, the present study was performed to determine whether physiological downregulation of the NPC1 gene/protein alters the transport and metabolism of low-density lipoprotein (LDL)-derived cholesterol in human fibroblasts. To perform this study, three different culture conditions were used that included fibroblasts grown in lipoprotein-deficient serum (LPDS), LPDS supplemented with LDL, and LPDS supplemented with LDL, followed by equilibration in the absence of LDL to allow the transport of LDL-derived cholesterol from endocytic compartments and equilibration of cellular sterol pools. The results from this study indicated that in addition to the NPC1 gene/protein, the NPC2 gene/protein was also downregulated by LDL-derived cholesterol-dependent feedback inhibition and that downregulation of both the NPC1 and NPC2 genes/proteins was associated with the sequestration of LDL-derived cholesterol within endocytic compartments, including late endosomes/lysosomes after equilibration. Therefore, it is proposed that physiological and coordinate downregulation of the NPC1 and NPC2 genes/proteins promotes the sequestration of LDL-derived cholesterol within endocytic compartments and serves a role in maintaining intracellular cholesterol homeostasis.
authors.affiliation: Department of Pediatrics, The University of Arizona, 1501 N. Campbell Avenue, Tucson, Arizona 85724-5037, USA.
authors.forename: David
authors.initials: D
authors.lastname: Jelinek
authors.forename: Sarah Mount
authors.initials: SM
authors.lastname: Patrick
authors.forename: Khameeka N
authors.initials: KN
authors.lastname: Kitt
authors.forename: Teddy
authors.initials: T
authors.lastname: Chan
authors.forename: Gordon A
authors.initials: GA
authors.lastname: Francis
authors.forename: William S
authors.initials: WS
authors.lastname: Garver
mesh_terms: D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D008078:Cholesterol, LDL / Q000378:metabolism*; D015536:Down-Regulation; D011992:Endosomes / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D000077296:Niemann-Pick C1 Protein; D015398:Signal Transduction; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D008078:Cholesterol, LDL; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; C104585:NPC2 protein, human; D000077296:Niemann-Pick C1 Protein; D051779:Sterol Regulatory Element Binding Proteins; D033921:Vesicular Transport Proteins