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

Lipids in Health and Disease

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[1] 0000 0000 8517 6224, grid.275559.9, Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC), and the Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knöll-Str. 2, 07745, Jena, Germany;0000 0000 9737 0454, grid.413108.f, Institute of Anatomy, Rostock University Medical Center, Gertrudenstraße 9, 18057, Rostock, Germany;0000 0000 9737 0454, grid.413108.f, Institute of Anatomy, Rostock University Medical Center, Gertrudenstraße 9, 18057, Rostock, Germany;0000 0001 1009 3608, grid.5560.6, Research Group Anatomy, School of Medicine and Health Sciences, Department für Humanmedizin, Abteilung Anatomie, Carl von Ossietzky University Oldenburg, Carl-von-Ossietzky Straße 9-11, 26129, Oldenburg, Germany;0000 0000 9737 0454, grid.413108.f, Institute of Anatomy, Rostock University Medical Center, Gertrudenstraße 9, 18057, Rostock, Germany;0000 0001 1009 3608, grid.5560.6, Research Group Anatomy, School of Medicine and Health Sciences, Department für Humanmedizin, Abteilung Anatomie, Carl von Ossietzky University Oldenburg, Carl-von-Ossietzky Straße 9-11, 26129, Oldenburg, Germany;0000 0001 1009 3608, grid.5560.6, Research Center for Neurosensory Science, Carl von Ossietzky University Oldenburg, Oldenburg, Germany;0000 0000 9737 0454, grid.413108.f, Institute of Clinical Chemistry and Pathobiochemistry, Rostock University Medical Center, Ernst-Heydemann-Straße 6, 18057, Rostock, Germany;0000 0000 9737 0454, grid.413108.f, Institute of Immunology, Rostock University Medical Center, Schillingallee 70, 18057, Rostock, Germany;0000 0000 9737 0454, grid.413108.f, Medical Biology and Electron Microscopy Center, Rostock University Medical Center, Strempelstraße 14, 18057, Rostock, Germany;0000 0001 1009 3608, grid.5560.6, Human Genetics, Faculty of Medicine and Health Sciences, University of Oldenburg, Oldenburg, Germany;0000 0001 1009 3608, grid.5560.6, Research Center for Neurosensory Science, Carl von Ossietzky University Oldenburg, Oldenburg, Germany;Centogene AG, Am Strande 7, 18055, Rostock, Germany;

关键词: Niemann-pick disease type C1;    Spleen;    Phospholipids;    PRGs;    G-protein-coupling receptor;    qRT-PCR;    S1P;    HPTLC;    Lymphocyte;   

DOI  :  10.1186/s12944-019-1088-2

来源: publisher

【 摘 要 】

BackgroundNiemann-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.MethodsHere, 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.ResultsDisease 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.ConclusionsIn summary, the treatment promotes normal spleen morphology, stabilization of lipid homeostasis and blocking of inflammation, but alters the composition of T cell subtypes.

【 授权许可】

CC BY