Type C Niemann-Pick disease: use of hydrophobic amines to study defective cholesterol transport

• Published in: Developmental neuroscience Vol. 13; no. 4-5; p. 315
• Main Authors: Roff, C F, Goldin, E, Comly, M E, Cooney, A, Brown, A, Vanier, M T, Miller, S P, Brady, R O, Pentchev, P G
• Format: Journal Article
• Language: English
• Published: Switzerland 01-01-1991
• Subjects: Amines - pharmacology; Androstenes - pharmacology; Animals; Biological Transport - drug effects; Cells, Cultured; Cholesterol - metabolism; Cholesterol Esters - biosynthesis; Disease Models, Animal; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Filipin; Humans; Imipramine - pharmacology; Lysosomes - drug effects; Lysosomes - metabolism; Mice; Morpholines - pharmacology; Niemann-Pick Diseases - classification; Niemann-Pick Diseases - metabolism; Niemann-Pick Diseases - pathology; Sphingosine - analogs & derivatives; Sphingosine - pharmacology; Structure-Activity Relationship
• ISSN: 0378-5866
• DOI: 10.1159/000112179

Niemann-Pick Type C (NPC) disease is a cholesterol lipidosis resulting from defective postlysosomal cholesterol transport. In normal cells this segment of cholesterol trafficking is inhibited by treatment with either U18666A or imipramine. Other compounds are also capable of blocking postlysosomal cholesterol transport: stearylamine, RV-538, and sphinganine inhibit low-density lipoprotein-induced esterification of cholesterol and cause unesterified cholesterol to accumulate in perinuclear vesicles. These vesicles can be stained with filipin to give a staining pattern indistinguishable from that seen in NPC fibroblasts. Because all of these compounds are hydrophobic amines, we conclude that most, if not all, hydrophobic amines block the postlysosomal transport of cholesterol. These results also raise the possibility that an endogenous amine, e.g., sphinganine, may inhibit cholesterol transport in NPC.