Evidence map›Paper›PMID 39395801›Full record

ArticleThe Journal of biological chemistry2024

Molecular determinants of phospholipid treatment to reduce intracellular cholesterol accumulation in NPC1 deficiency.

Shikun Deng, Ting-Ann Liu, Olga Ilnytska, Tamara Allada, Angelina Fomina, Nancy Lin, Valentina Z Petukhova, Koralege C Pathmasiri, Kiran Chinthapally, Brian S J Blagg and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of biological chemistry, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Shikun DengDepartment of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey, USA.
Ting-Ann LiuDepartment of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey, USA.
Olga IlnytskaDepartment of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey, USA; Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey, USA.
Tamara AlladaDepartment of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey, USA.
Angelina FominaDepartment of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey, USA.
Nancy LinDepartment of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey, USA; Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey, USA.
Valentina Z PetukhovaDepartment of Chemistry, University of Illinois Chicago, Chicago, Illinois, USA.
Koralege C PathmasiriDepartment of Chemistry, University of Illinois Chicago, Chicago, Illinois, USA.
Kiran ChinthapallyWarren Center for Drug Discovery and Development, and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
Brian S J BlaggWarren Center for Drug Discovery and Development, and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
Brandon L AshfeldWarren Center for Drug Discovery and Development, and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
Stephanie M ColognaDepartment of Chemistry, University of Illinois Chicago, Chicago, Illinois, USA.
Judith StorchDepartment of Nutritional Sciences, Rutgers University, New Brunswick, New Jersey, USA; Rutgers Center for Lipid Research, Rutgers University, New Brunswick, New Jersey, USA. Electronic address: storch@sebs.rutgers.edu.

Funding

Development of autophagy modulators for evaluation as a therapeutic strategy for Niemann-Pick Type CR01NS114413 · NINDS · UNIVERSITY OF ILLINOIS AT CHICAGO · PI COLOGNA, STEPHANIE M · 2020 to 2024
$2.0M
Mechanisms of Cholesterol Transport by NPC ProteinsR01GM115866 · NIGMS · RUTGERS, THE STATE UNIV OF N.J. · PI STORCH, JUDITH · 2016 to 2019
$1.1M
NIGMS NIH HHS R01 GM115866NINDS NIH HHS R01 NS114413
6 · The paper itself

Abstract

Niemann-Pick type C (NPC) disease, caused by mutations in the NPC1 or NPC2 genes, leads to abnormal intracellular cholesterol accumulation in late endosomes/lysosomes. Exogenous enrichment with lysobisphosphatidic acid (LBPA), also known as bis-monoacylglycerol phosphate, either directly or via the LBPA precursor phosphatidylglycerol (PG), has been investigated as a therapeutic intervention to reduce cholesterol accumulation in NPC disease. Here, we report the effects of stereoisomer configuration and acyl chain composition of LBPA on cholesterol clearance in NPC1-deficient cells. We find that S,R, S,S, and S,R LBPA stereoisomers behaved similarly, with all 3 compounds leading to comparable reductions in filipin staining in two NPC1-deficient human fibroblast cell lines. Examination of several LBPA molecular species containing one or two monounsaturated or polyunsaturated acyl chains showed that all LBPA species containing one 18:1 chain significantly reduced cholesterol accumulation, whereas the shorter chain species di-14:0 LBPA had little effect on cholesterol clearance in NPC1-deficient cells. Since cholesterol accumulation in NPC1-deficient cells can also be cleared by PG incubation, we used nonhydrolyzable PG analogs to determine whether conversion to LBPA is required for sterol clearance, or whether PG itself is effective. The results showed that nonhydrolyzable PG species were not appreciably converted to LBPA and showed virtually no cholesterol clearance efficacy in NPC1-deficient cells, supporting the notion that LBPA is the active agent promoting late endosome/lysosome cholesterol clearance. Overall these studies are helping to define the molecular requirements for potential therapeutic use of LBPA as an option for addressing NPC disease.

Indexed as

CholesterolFibroblastsIntracellular Signaling Peptides and ProteinsLysophospholipidsMonoglyceridesNiemann-Pick C1 ProteinNiemann-Pick Disease, Type CCarrier ProteinsCell LineEndosomesHumansLysosomesMembrane Glycoproteinsbis(monoacylglyceryl)phosphateCarrier ProteinsCholesterolIntracellular Signaling Peptides and ProteinsLysophospholipidsMembrane GlycoproteinsMonoglyceridesNiemann-Pick C1 ProteinNPC1 protein, humanbis-monoacylglycerol phosphatecholesterollysobisphosphatidic acidlysosomeNiemann-Pick C diseasephosphatidylglycerolphospholipid

Identifiers

PMID39395801
PMCPMC11650715

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.