{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T17:34:51Z","timestamp":1792604091317,"version":"4.5.0"},"reference-count":30,"publisher":"National Academy of Sciences","issue":"7","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,2,17]]},"abstract":"\n Niemann-Pick type C disease is largely attributable to an inactivating mutation of NPC1 protein, which normally aids movement of unesterified cholesterol (C) from the endosomal\/lysosomal (E\/L) compartment to the cytosolic compartment of cells throughout the body. This defect results in activation of macrophages in many tissues, progressive liver disease, and neurodegeneration. In the\n npc1<\/jats:italic>\n \u2212\/\u2212<\/jats:sup>\n mouse, a model of this disease, the whole-animal C pool expands from 2,082 to 4,925 mg\/kg body weight (bw) and the hepatic C pool increases from 132 to 1,485 mg\/kg bw between birth and 49 days of age. A single dose of 2-hydroxypropyl-\u03b2-cyclodextrin (CYCLO) administered at 7 days of age immediately caused this sequestered C to flow from the lysosomes to the cytosolic pool in many organs, resulting in a marked increase in cholesteryl esters, suppression of C but not fatty acid synthesis, down-regulation of genes controlled by sterol regulatory element 2, and up-regulation of many liver X receptor target genes. There was also decreased expression of proinflammatory proteins in the liver and brain. In the liver, where the rate of C sequestration equaled 79 mg\u00b7d\n \u22121<\/jats:sup>\n \u00b7kg\n \u22121<\/jats:sup>\n , treatment with CYCLO within 24 h increased C movement out of the E\/L compartment from near 0 to 233 mg\u00b7d\n \u22121<\/jats:sup>\n \u00b7kg\n \u22121<\/jats:sup>\n . By 49 days of age, this single injection of CYCLO resulted in a reduction in whole-body C burden of >900 mg\/kg, marked improvement in liver function tests, much less neurodegeneration, and, ultimately, significant prolongation of life. These findings suggest that CYCLO acutely reverses the lysosomal transport defect seen in NPC disease.\n <\/jats:p>","DOI":"10.1073\/pnas.0810895106","type":"journal-article","created":{"date-parts":[[2009,1,26]],"date-time":"2009-01-26T20:45:51Z","timestamp":1233002751000},"page":"2377-2382","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":357,"title":["Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the\n npc1<\/i>\n \u2212\/\u2212<\/sup>\n mouse"],"prefix":"10.1073","volume":"106","author":[{"given":"Benny","family":"Liu","sequence":"first","affiliation":[{"name":"Departments of aInternal Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen D.","family":"Turley","sequence":"additional","affiliation":[{"name":"Departments of aInternal Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis K.","family":"Burns","sequence":"additional","affiliation":[{"name":"Pathology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna M.","family":"Miller","sequence":"additional","affiliation":[{"name":"PhysiologyUniversity of Texas Southwestern Medical CenterDallasTX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce J.","family":"Repa","sequence":"additional","affiliation":[{"name":"Departments of aInternal Medicine,"},{"name":"PhysiologyUniversity of Texas Southwestern Medical CenterDallasTX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Dietschy","sequence":"additional","affiliation":[{"name":"Departments of aInternal Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,2,17]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5323.228"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.290.5500.2298"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M700125-JLR200"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1388-1981(00)00055-X"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.1999.276.2.E336"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5323.232"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.21.11992"},{"key":"e_1_3_3_8_2","first-page":"2625","volume-title":"The Metabolic and Molecular Bases of Inherited Disease","author":"Pentchev PG","year":"1995","unstructured":"PG Pentchev, MT Vanier, K Suzuki, MC Patterson, Niemann-Pick disease type C: A cellular cholesterol lipidosis. 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