scholarly journals Drug-induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann-Pick type C cells and mice

2018 ◽  
Author(s):  
Dimitri Moreau ◽  
Fabrizio Vacca ◽  
Stefania Vossio ◽  
Cameron Scott ◽  
Alexandria Colaco ◽  
...  
Keyword(s):  
Cholesteryl Ester ◽  
Free Cholesterol ◽  
C Cells ◽  
Drug Induced ◽  
Endosomal Membranes ◽  
Lysobisphosphatidic Acid ◽  
Type C ◽  
Niemann Pick ◽  
Cholesterol Storage ◽  
Histamine H3

ABSTRACTMost cells acquire cholesterol by endocytosis of circulating LDLs. After cholesteryl ester de-esterification in endosomes, free cholesterol is redistributed to intracellular membranes via unclear mechanisms. Our previous work suggested that the unconventional phospholipid lysobisphosphatidic acid (LBPA) may play a role in modulating the cholesterol flux through endosomes. In this study, we used the Prestwick library of FDA-approved compounds in a high content, image-based screen of the endosomal lipids, lysobisphosphatidic acid and LDL-derived cholesterol. We report that thioperamide maleate, an inverse agonist of the histamine H3 receptor HRH3, increases highly selectively the levels of lysobisphosphatidic acid, without affecting any endosomal protein or function that we tested. Our data also show that thioperamide significantly reduces the endosome cholesterol overload in fibroblasts from patients with the cholesterol storage disorder Niemann-Pick type C (NPC), as well as in liver ofNpc1−/−mice. We conclude that LBPA controls endosomal cholesterol mobilization and export to cellular destinations, perhaps by fluidifying or buffering cholesterol in endosomal membranes, and that thioperamide has repurposing potential for the treatment of NPC.

scholarly journals Drug‐induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann–Pick type C cells and mice

EMBO Reports ◽  
2019 ◽  
Vol 20 (7) ◽  
Author(s):  
Dimitri Moreau ◽  
Fabrizio Vacca ◽  
Stefania Vossio ◽  
Cameron Scott ◽  
Alexandria Colaco ◽  
...  
Keyword(s):  
C Cells ◽  
Drug Induced ◽  
Lysobisphosphatidic Acid ◽  
Type C ◽  
Niemann Pick

scholarly journals Cyclodextrin triggers MCOLN1-dependent endo-lysosome secretion in Niemann-Pick type C cells

2018 ◽  
Author(s):  
Fabrizio Vacca ◽  
Stefania Vossio ◽  
Vincent Mercier ◽  
Dimitri Moreau ◽  
Shem Johnson ◽  
...  
Keyword(s):  
Storage Disease ◽  
Cell Types ◽  
Cytosolic Calcium ◽  
C Cells ◽  
Low Concentrations ◽  
Transient Rise ◽  
Type C ◽  
Niemann Pick ◽  
Lysosome Related Organelles ◽  
Cholesterol Storage

ABSTRACTIn specialized cell types, lysosome-related organelles support regulated secretory pathways, while in non-specialized cells, lysosomes can undergo fusion with the plasma membrane in response to a transient rise in cytosolic calcium. Recent evidence also indicates that lysosome secretion can be controlled transcriptionally and promote clearance in lysosome storage diseases. In addition, evidence is also accumulating that low concentrations of cyclodextrins reduce the cholesterol storage phenotype in cells and animals with the cholesterol storage disease Niemann-Pick type C, via an unknown mechanism. Here, we report that cyclodextrin triggers the secretion of the endo/lysosomal content in non-specialized cells, and that this mechanism is responsible for the decreased cholesterol overload in Niemann-Pick type C cells. We also find that that the secretion of the endo/lysosome content occurs via a mechanism dependent on the endosomal calcium channel MCOLN1, as well as FYCO1, the AP1 adaptor and its partner Gadkin. We conclude that endolysosomes in non-specialized cells can acquire secretory functions elicited by cyclodextrin, and that this pathway is responsible for the decrease in cholesterol storage in Niemann-Pick C cells.

scholarly journals In vivo Efficacy and Safety Evaluation of Lactosyl-β-cyclodextrin as a Therapeutic Agent for Hepatomegaly in Niemann-Pick Type C Disease

Nanomaterials ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 802 ◽  
Author(s):  
Yuki Maeda ◽  
Keiichi Motoyama ◽  
Rena Nishiyama ◽  
Taishi Higashi ◽  
Risako Onodera ◽  
...  
Keyword(s):  
Free Cholesterol ◽  
Subcutaneous Administration ◽  
Safety Evaluation ◽  
Autosomal Recessive Disorder ◽  
Liver Cells ◽  
High Dose ◽  
Efficacy And Safety ◽  
Type C ◽  
Niemann Pick

Niemann-Pick type C disease (NPC) is a fatal, autosomal recessive disorder, which causes excessive accumulation of free cholesterol in endolysosomes, resulting in progressive hepatomegaly and neurodegeneration. Currently, 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) is used at a high dose for the treatment of NPC, risking lung toxicity and hearing loss during treatment. One method to reduce the required dose of HP-β-CyD for the treatment of hepatomegaly is to actively deliver β-cyclodextrin (β-CyD) to hepatocytes. Previously, we synthesized lactosyl-β-CyD (Lac-β-CyD) and demonstrated that it lowers cholesterol in NPC model liver cells. In the present study, we studied the efficacy and safety of Lac-β-CyD treatment of hepatomegaly in Npc1−/− mice. After subcutaneous administration, Lac-β-CyD accumulated in the liver and reduced hepatomegaly with greater efficacy than HP-β-CyD. In addition, subcutaneous administration of a very high dose of Lac-β-CyD was less toxic to the lungs than HP-β-CyD. Notably, the accumulation of intracellular free cholesterol in endolysosomes of NPC-like liver cells was significantly lower after administration of Lac-β-CyD than after treatment with HP-β-CyD. In conclusion, these results suggest that Lac-β-CyD is a candidate for the effective treatment of hepatomegaly in NPC.

scholarly journals Cholesterol Movement in Niemann-Pick Type C Cells and in Cells Treated with Amphiphiles

2000 ◽  
Vol 275 (23) ◽  
pp. 17468-17475 ◽  
Author(s):  
Yvonne Lange ◽  
Jin Ye ◽  
Mike Rigney ◽  
Theodore Steck
Keyword(s):  
C Cells ◽  
Type C ◽  
Niemann Pick ◽  
In Cells

A High-Content RNAi-Screening Assay to Identify Modulators of Cholesterol Accumulation in Niemann–Pick Type C Cells

2010 ◽  
Vol 8 (3) ◽  
pp. 295-319 ◽  
Author(s):  
Shilpi Arora ◽  
Christian Beaudry ◽  
Kristen M. Bisanz ◽  
Chao Sima ◽  
Jeffrey A. Kiefer ◽  
...  
Keyword(s):  
C Cells ◽  
Cholesterol Accumulation ◽  
Screening Assay ◽  
Rnai Screening ◽  
Type C ◽  
Niemann Pick

scholarly journals The Tetraspanin CD63/lamp3 Cycles between Endocytic and Secretory Compartments in Human Endothelial Cells

2000 ◽  
Vol 11 (5) ◽  
pp. 1829-1843 ◽  
Author(s):  
Toshihide Kobayashi ◽  
Ulrich M. Vischer ◽  
Corinne Rosnoblet ◽  
Cécile Lebrand ◽  
Margaret Lindsay ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasma Membrane ◽  
Late Endosome ◽  
Human Endothelial Cells ◽  
Late Endosomes ◽  
Lysobisphosphatidic Acid ◽  
Type C ◽  
Niemann Pick ◽  
Tetraspanin Cd63

In the present study, we show that in human endothelial cells the tetraspanin CD63/lamp3 distributes predominantly to the internal membranes of multivesicular–multilamellar late endosomes, which contain the unique lipid lysobisphosphatidic acid. Some CD63/lamp3 is also present in Weibel–Palade bodies, the characteristic secretory organelle of these cells. We find that CD63/lamp3 molecules can be transported from late endosomes to Weibel–Palade bodies and thus that CD63/lamp3 cycles between endocytic and biosynthetic compartments; however, movement of CD63/lamp3 is much slower than that of P-selectin, which is known to cycle between plasma membrane and Weibel–Palade bodies. When cells are treated with U18666A, a drug that mimics the Niemann-Pick type C syndrome, both proteins accumulate in late endosomes and fail to reach Weibel–Palade bodies efficiently, suggesting that P-selectin, like CD63/lamp3, cycles via late endosomes. Our data suggest that CD63/lamp3 partitions preferentially within late endosome internal membranes, thus causing its accumulation, and that this mechanism contributes to CD63/lamp3 retention in late endosomes; however, our data also indicate that the protein can eventually escape from these internal membranes and recycle toward Weibel–Palade bodies to be reused. Our observations thus uncover the existence of a selective trafficking route from late endosomes to Weibel–Palade bodies.

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