Targeting defective sphingosine kinase 1 in Niemann?Pick type C disease with an activator mitigates cholesterol accumulation

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62157124%3A16370%2F20%3A43878615" target="_blank" >RIV/62157124:16370/20:43878615 - isvavai.cz</a>

Alternative codes found

RIV/00216224:14160/20:00118106

Result on the web

<a href="https://www.sciencedirect.com/science/article/pii/S0021925817503336?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0021925817503336?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1074/jbc.RA120.012659" target="_blank" >10.1074/jbc.RA120.012659</a>

Result language

angličtina

Original language name

Targeting defective sphingosine kinase 1 in Niemann?Pick type C disease with an activator mitigates cholesterol accumulation

Original language description

Niemann?Pick type C (NPC) disease is a lysosomal storage disorder arising from mutations in the cholesterol-trafficking protein NPC1 (95%) or NPC2 (5%). These mutations result in accumulation of low-density lipoprotein-derived cholesterol in late endosomes/lysosomes, disruption of endocytic trafficking, and stalled autophagic flux. Additionally, NPC disease results in sphingolipid accumulation, yet it is unique among the sphingolipidoses because of the absence of mutations in the enzymes responsible for sphingolipid degradation. In this work, we examined the cause for sphingosine and sphingolipid accumulation in multiple cellular models of NPC disease and observed that the activity of sphingosine kinase 1 (SphK1), one of the two isoenzymes that phosphorylate sphingoid bases, was markedly reduced in both NPC1 mutant and NPC1 knockout cells. Conversely, SphK1 inhibition with the isotype-specific inhibitor SK1-I in WT cells induced accumulation of cholesterol and reduced cholesterol esterification. Of note, a novel SphK1 activator (SK1-A) that we have characterized decreased sphingoid base and complex sphingolipid accumulation and ameliorated autophagic defects in both NPC1 mutant and NPC1 knockout cells. Remarkably, in these cells, SK1-A also reduced cholesterol accumulation and increased cholesterol ester formation. Our results indicate that a SphK1 activator rescues aberrant cholesterol and sphingolipid storage and trafficking in NPC1 mutant cells. These observations highlight a previously unknown link between SphK1 activity, NPC1, and cholesterol trafficking and metabolism.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10608 - Biochemistry and molecular biology

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Biological Chemistry

ISSN

0021-9258

e-ISSN

—

Volume of the periodical

295

Issue of the periodical within the volume

27

Country of publishing house

US - UNITED STATES

Number of pages

13

Pages from-to

9121-9133

UT code for WoS article

000550698000020

EID of the result in the Scopus database

—