A therapy with miglustat, 2-hydroxypropyl-ß-cyclodextrin and allopregnanolone restores splenic cholesterol homeostasis in Niemann-pick disease type C1

Autor: Neßlauer, Anna-Maria, Gläser, Anne, Gräler, Markus, Engelmann, Robby, Müller-Hilke, Brigitte, Frank, Marcus, Burstein, Christine, Rolfs, Arndt, Neidhardt, John, Wree, Andreas, Witt, Martin, Bräuer, Anja U.
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Lipids in Health and Disease
Lipids in Health and Disease, Vol 18, Iss 1, Pp 1-18 (2019)
ISSN: 1476-511X
Popis: Background Niemann-Pick disease type C1 (NPC1) is an autosomal-recessive lipid-storage disorder with an estimated minimal incidence of 1/120,000 live births. Besides other neuronal and visceral symptoms, NPC1 patients develop spleen dysfunction, isolated spleno- or hepatosplenomegaly and infections. The mechanisms of splenomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood. Methods Here, we used an NPC1 mouse model to study a splenoprotective effect of a treatment with miglustat, 2-hydroxypropyl-ß-cyclodextrin and allopregnanolone and showed that this treatment has a positive effect on spleen morphology and lipid metabolism. Results Disease progress can be halted and blocked at the molecular level. Mutant Npc1 (Npc1−/−) mice showed increased spleen weight and increased lipid accumulation that could be avoided by our treatment. Also, FACS analyses showed that the increased number of splenic myeloid cells in Npc1−/− mice was normalized by the treatment. Treated Npc1−/− mice showed decreased numbers of cytotoxic T cells and increased numbers of T helper cells. Conclusions In summary, the treatment promotes normal spleen morphology, stabilization of lipid homeostasis and blocking of inflammation, but alters the composition of T cell subtypes. Electronic supplementary material The online version of this article (10.1186/s12944-019-1088-2) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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