Identification of Niemann-Pick C1 disease biomarkers through sphingolipid profiling

Fan, Martin; Sidhu, Rohini; Fujiwara, Hideji; Tortelli, Brett A.; Zhang, Jessie; Davidson, Cristin; Walkley, Steven U.; Bagel, Jessica H.; Vite, Charles H.; Yanjanin, Nicole M.; Porter, Forbes D.; Schaffer, Jean E.; Ory, Daniel S.

doi:10.1194/jlr.m040618

Cited by 94 publications

(109 citation statements)

References 48 publications

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“…This phenotype is also observed in the mouse model of NiemannPick disease type C, a lysosomal storage disorder presenting as an accumulation of cholesterol and sphingolipids in the lysosome and decreased concentrations of circulating S1P in human patients ( 96,97 ). Studies utilizing FTY720 indicated that S1P 1 also contributes to NK cell migration from LN to lymph, but the contribution is relatively minor compared with that of S1P 5 , which is not subject to CD69 regulation ( 75,94 ).…”

Section: Immune Systemmentioning

confidence: 85%

An update on the biology of sphingosine 1-phosphate receptors

Blaho

Hla

2014

Journal of Lipid Research

454

403

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This article is available online at http://www.jlr.org during development and ageing. S1P 1 , S1P 2 , and S1P 3 are essentially ubiquitously expressed, whereas expression of S1P 4 and S1P 5 are highly restricted to distinct cell types ( 4 ).Production of S1P can be initiated by external or internal signals, which lead to activation of the biosynthetic pathway beginning with metabolism of membrane SM to ceramide by SMases ( 5, 6 ). Ceramide, an important signaling molecule itself, can be metabolized by ceramidase to sphingosine (Sph) ( 7 ). Sph is then phosphorylated by one of two Sph kinases (Sphks), Sphk1 or Sphk2, resulting in S1P genesis ( 8-10 ) ( Fig. 1 ).Although there are proposed intracellular roles for S1P, it is often transported out of the cell where it can act in an autocrine or paracrine manner on S1PRs ( 11, 12 ). Transport out of the cell may occur via several transporters; however, the only bona fi de transporter to date is spinster 2, which is also capable of FTY720 (fi ngolimod/Gilenya; Novartis) export (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Once outside of the cell, S1P can bind to two known carriers, albumin or ApoM ( 6, 23, 24 ) ( Fig. 1 ). Approximately 35% of plasma S1P is bound to albumin and 65% to ApoM, which is found on a small percentage ( ‫ف‬ 5%) of HDL particles ( 24 ). This ApoM+HDL-bound S1P has been proposed as a primary contributor to the vasoprotective properties of HDLs ( 25-27 ). How albumin or ApoM deliver S1P to specifi c S1PRs has yet to be characterized. AGONISTS AND ANTAGONISTSThere are several well-characterized agonists and antagonists of S1PRs; however, most compounds have been diAbstract Sphingosine 1-phosphate (S1P) is a membranederived lysophospholipid that acts primarily as an extracellular signaling molecule. Signals initiated by S1P are transduced by five G protein-coupled receptors, named S1P 1-5 . Cellular and temporal expression of the S1P receptors (S1PRs) determine their specifi c roles in various organ systems, but they are particularly critical for regulation of the cardiovascular, immune, and nervous systems, with the most well-known contributions of S1PR signaling being modulation of vascular barrier function, vascular tone, and regulation of lymphocyte traffi cking. However, our knowledge of S1PR biology is rapidly increasing as they become attractive therapeutic targets in several diseases, such as chronic infl ammatory pathologies, autoimmunity, and cancer. Understanding how the S1PRs regulate interactions between biological systems will allow for greater effi cacy in this novel therapeutic strategy as well as characterization of complex physiological networks. Because of the rapidly expanding body of research, this review will focus on the most recent advances in S1PRs. Sphingosine 1-phosphate [2 S -amino-1-(dihydrogen phosphate)-4E-octadecene-1,3 R -diol] (S1P) is a simple membrane-derived lysophospholipid with regulatory roles in almost all facets of mammalian biology ( 1 ). Concentrations of S1P in blood and lymph plasmas are high, in the high...

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Section: Immune Systemmentioning

confidence: 85%

An update on the biology of sphingosine 1-phosphate receptors

Blaho

Hla

2014

Journal of Lipid Research

454

403

View full text Add to dashboard Cite

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“…An important consideration when testing therapies for NPC disease patients is how disease progression can be quantitatively assessed. Thus, validation of biomarkers of NPC disease progression is an important goal (147)(148)(149). Because gangliosides accumulate in LEs/Ls of NPC-defi cient cells, miglustat, which effi ciently crosses the blood-brain barrier, has been used for treatment of NPC patients.…”

Section: Cyclodextrin As a Therapy For Npc Diseasementioning

confidence: 99%

Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

Vance

Karten

2014

Journal of Lipid Research

147

125

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“…As a consequence of this defect along with unesterified cholesterol, a large number of different complex sphingolipids accumulate with differing organ specificity in both NP-C patients and animal models [1,16,17,18]. This led to the hypothesis that a panel of lysosphingolipids may be useful as biomarkers in NP-C.…”

Section: Introductionmentioning

confidence: 99%