Article ; Online: Altered vitamin E status in Niemann-Pick type C disease.
2011 Volume 52, Issue 7, Page(s) 1400–1410
Abstract: Vitamin E (α-tocopherol) is the major lipid-soluble antioxidant in many species. Niemann-Pick type ... C (NPC) disease is a lysosomal storage disorder caused by mutations in the NPC1 or NPC2 gene ... NPC2 expression or function in cultured cells caused a marked lysosomal accumulation of vitamin E ...
| Abstract | Vitamin E (α-tocopherol) is the major lipid-soluble antioxidant in many species. Niemann-Pick type C (NPC) disease is a lysosomal storage disorder caused by mutations in the NPC1 or NPC2 gene, which regulates lipid transport through the endocytic pathway. NPC disease is characterized by massive intracellular accumulation of unesterified cholesterol and other lipids in lysosomal vesicles. We examined the roles that NPC1/2 proteins play in the intracellular trafficking of tocopherol. Reduction of NPC1 or NPC2 expression or function in cultured cells caused a marked lysosomal accumulation of vitamin E in cultured cells. In vivo, tocopherol significantly accumulated in murine Npc1-null and Npc2-null livers, Npc2-null cerebella, and Npc1-null cerebral cortices. Plasma tocopherol levels were within the normal range in Npc1-null and Npc2-null mice, and in plasma samples from human NPC patients. The binding affinity of tocopherol to the purified sterol-binding domain of NPC1 and to purified NPC2 was significantly weaker than that of cholesterol (measurements kindly performed by R. Infante, University of Texas Southwestern Medical Center, Dallas, TX). Taken together, our observations indicate that functionality of NPC1/2 proteins is necessary for proper bioavailability of vitamin E and that the NPC pathology might involve tissue-specific perturbations of vitamin E status. |
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| MeSH term(s) | Alleles ; Animals ; Biological Transport ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Line ; Extracellular Space/metabolism ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Gene Expression Regulation/genetics ; Gene Knockdown Techniques ; Glycoproteins/deficiency ; Glycoproteins/genetics ; Glycoproteins/metabolism ; Hepatocytes/cytology ; Hepatocytes/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins ; Ligands ; Lysosomes/metabolism ; Membrane Glycoproteins/deficiency ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism ; Mice ; Niemann-Pick Disease, Type C/genetics ; Niemann-Pick Disease, Type C/metabolism ; Niemann-Pick Disease, Type C/pathology ; Vesicular Transport Proteins ; alpha-Tocopherol/metabolism |
| Chemical Substances | Carrier Proteins ; Glycoproteins ; Intracellular Signaling Peptides and Proteins ; Ligands ; Membrane Glycoproteins ; NPC1 protein, human ; NPC2 protein, human ; Vesicular Transport Proteins ; alpha-Tocopherol (H4N855PNZ1) |
| Language | English |
| Publishing date | 2011-05-05 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 80154-9 |
| ISSN | 1539-7262 ; 0022-2275 |
| ISSN (online) | 1539-7262 |
| ISSN | 0022-2275 |
| DOI | 10.1194/jlr.M015560 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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