title: Niemann-Pick C1 protein regulates cholesterol transport to the trans-Golgi network and plasma membrane caveolae.
abstract: The Niemann-Pick C1 (NPC1) protein regulates cholesterol transport from late endosomes-lysosomes to other intracellular compartments. In this article, cholesterol transport to caveolin-1 and caveolin-2 containing compartments, such as the trans-Golgi network (TGN) and plasma membrane caveolae, was examined in normal (NPC+/+), NPC heterozygous (NPC+/-), and NPC homozygous (NPC-/-) human fibroblasts. The expression and distribution of NPC1 in each cell type were similar, and characterized by a finely dispersed, granular staining pattern. The expression of caveolin-1 and caveolin-2 was increased in NPC+/- and NPC-/- fibroblasts, although the distribution in each cell type was similar and characterized by predominant staining of the TGN and plasma membrane. The TGN in NPC+/+ fibroblasts was relatively cholesterol-enriched, whereas the TGN in NPC+/- and NPC-/- fibroblasts was partially or completely cholesterol-deficient, respectively. Consistent with studies demonstrating the transport of cholesterol from the TGN to plasma membrane caveolae, the concentration of cholesterol in plasma membrane caveolae isolated from NPC+/- and NPC-/- fibroblasts was significantly decreased, even though the total concentration of plasma membrane cholesterol in each cell type was similar. These studies demonstrate that NPC1 regulates cholesterol transport to caveolin-1 and caveolin-2 containing compartments such as the TGN and plasma membrane caveolae.
authors.affiliation: Department of Pediatrics, Arizona Health Sciences Center, The University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA. wgarver@peds.arizona.edu
authors.forename: William S
authors.initials: WS
authors.lastname: Garver
authors.forename: Kumar
authors.initials: K
authors.lastname: Krishnan
authors.forename: Jayme R
authors.initials: JR
authors.lastname: Gallagos
authors.forename: Makoto
authors.initials: M
authors.lastname: Michikawa
authors.forename: Gordon A
authors.initials: GA
authors.lastname: Francis
authors.forename: Randall A
authors.initials: RA
authors.lastname: Heidenreich
mesh_terms: D001692:Biological Transport; D002352:Carrier Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D021941:Caveolae / Q000737:chemistry / Q000378:metabolism*; D051242:Caveolin 1; D051243:Caveolin 2; D022461:Caveolins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D000077296:Niemann-Pick C1 Protein; D021601:trans-Golgi Network / Q000378:metabolism*
chemical_list: C495540:CAV1 protein, human; D002352:Carrier Proteins; D051242:Caveolin 1; D051243:Caveolin 2; D022461:Caveolins; C053330:Golgi membrane glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D002784:Cholesterol