Sphingosine 1-Phosphate (S1P) Lyase Deficiency Increases Sphingolipid Formation via Recycling at the Expense of de Novo Biosynthesis in Neurons

Hagen-Euteneuer, Nadine; Lütjohann, Dieter; Park, Hye-Jung; Merrill, Alfred H.; Echten‐Deckert, Gerhild van

doi:10.1074/jbc.m111.302380

Cited by 47 publications

(44 citation statements)

References 40 publications

(50 reference statements)

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“…This result indicates that sphingadienine can be metabolized to ceramide in intestinal cells during absorption. As phosphorylation followed by dephosphorylation is required for the incorporation of exogenous sphingoid bases into complex sphingolipids (33,34), 4t,8c-sphingadienene should be phosphorylated by sphingosine kinase after uptake by intestinal cells.…”

Section: Discussionmentioning

confidence: 99%

Selective Absorption of Dietary Sphingoid Bases from the Intestine via Efflux by P-Glycoprotein in Rats

Fujii

Manabe

Aida

et al. 2017

J Nutr Sci Vitaminol

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Summary Various physiological functions of dietary sphingolipids, such as preventing inflammation and improving the skin barrier function, have been recently demonstrated. The sphingolipid most commonly used as a foodstuff is glucosylceramide from plant sources, which is composed of sphingoid bases that are distinctive from those found in mammals. Although the structure of sphingoid bases in higher plants is more complicated than the structure of those in mammals, the fate of dietary sphingolipids of plant origin is still not understood. In the present study, we investigated the absorption of 4,8-sphingadienine that originated from maize glucosylceramide in the rat intestine by using a lipid absorption assay of lymph collected from the thoracic duct. The cumulative recovery of 4,8-sphingadienine in the lymph was lower than that of sphingosine. Verapamil, a P-glycoprotein inhibitor, significantly increased the absorption of 4,8-sphingadienine but did not affect the absorption of sphingosine. Plant-derived sphingoid bases were detected in the ceramide fraction of lymph fluid by using liquid chromatography-mass spectrometry analysis. These results indicate that 4,8-sphingadienine that originates from the glucosylceramide of higher plants is poorly absorbed in the intestine because of efflux by P-glycoprotein and can be incorporated into a ceramide moiety, at least in part, in intestinal endothelial cells. Key Words sphingolipids, sphingoid bases, sphingadienine, intestinal absorption, P-glycoprotein Sphingolipids are ubiquitous in all eukaryotic organisms and constitute a family of compounds that have a sphingoid base with an amide-linked fatty acid and a polar head group. Sphingolipids, having various structures of sphingoid bases, are ingested daily from foodstuffs because of the diverse structures of sphingoid bases that occur in nature. The most common sphingoid base of mammalian sphingolipids is sphingosine (trans-4-sphingenine, d18:1 4t ). Smaller amounts of other sphingoid bases such as sphinganine (dihydrosphingosine, d18:0) and phytosphingosine (4-hydroxysphinganine, t18:0) are encountered frequently. In higher plants, the structures of sphingoid bases are more complicated than in mammals because they can be desaturated at the C8-position by D8-sphingolipid desaturase, yielding cis-and trans-isomers of D8-unsaturated sphingoid bases (d18:2 4t,8c (t) ). Dietary sphingolipids from various sources have been reported to have beneficial effects such as preventing cancer (1-3), reducing inflammatory responses (4), and lowering levels of plasma lipids (5, 6). Dietary plant sphingolipids with sphingoid bases distinct from those found in mammals are able to prevent the formation of aberrant crypt foci in 1,2-dimethylhydrazine-treated mice (7,8). In addition, the beneficial effects of dietary plant sphingolipids have been reported in patients with atopic eczema and in model mice of skin damage, although the compositions of sphingoid bases in the stratum corneum of mammals are quite different from those of dietary...

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Section: Discussionmentioning

confidence: 99%

Selective Absorption of Dietary Sphingoid Bases from the Intestine via Efflux by P-Glycoprotein in Rats

Fujii

Manabe

Aida

et al. 2017

J Nutr Sci Vitaminol

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“…4). Notably, the effect of S1PL deficiency on sphingolipid metabolism in neurons and cholesterol levels in the brain was rather slight when compared with that in liver and serum [69,73]. Thus, no significant changes of the content of ceramide, sphingomyelin and of glycosphingolipids in neurons could be detected [69].…”

Section: S1p - a Potential Mediator In The Pathogenesis Of Alzheimer'mentioning

confidence: 99%

“…As depicted above, growing evidence indicates that S1P, a bioactive catabolic intermediate of all sphingolipids might represent a potential link between ganglioside metabolism and neurodegeneration. Neuronal levels of S1P are tightly regulated at very low concentrations in the picomolar range [18,69]. A direct role of S1P in neuronal Aβ generation has been reported recently [23].…”

Section: S1p - a Potential Mediator In The Pathogenesis Of Alzheimer'mentioning

confidence: 99%

Sphingosine-1-Phosphate: Boon and Bane for the Brain

Echten‐Deckert

Hagen-Euteneuer

Karaca

et al. 2014

Cell Physiol Biochem

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Sphingosine-1-phosphate (S1P), an evolutionary conserved bioactive lipid, is essential for brain development, but might also exert detrimental effects in terminally differentiated post-mitotic neurons. Its concentration in the brain is tightly regulated by specific kinases and phosphatases, and mainly by the S1P degrading enzyme, S1P-lyase (S1PL). The role of S1P in neurons was initially studied in primary cultures by using structural analogues. During the last 3 years generation of a S1PL deficient mouse model substantially promoted our knowledge on the functional role of S1P metabolism in the brain, and its potential relation to neurodegenerative diseases. However, our understanding of the molecular mechanisms that underlie the physiological and pathophysiological actions of S1P in neurons remains rather scarce.

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“…Also, cerebellar neurons derived from S1PL-KO mice, which have 20-fold increased concentrations of intracellular S1P, are more susceptible to certain stressors and undergo early cell death (23)(24)(25). Deficiency of S1P-lyase is also associated with elevated levels of basal intracellular Ca 2ϩ concentrations and increased stimulated Ca 2ϩ release from intracellular stores (25,26).…”

mentioning

confidence: 99%

Deficiency of Sphingosine-1-phosphate Lyase Impairs Lysosomal Metabolism of the Amyloid Precursor Protein

Karaca

Tamboli

Glebov

et al. 2014

Journal of Biological Chemistry

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Background: Sphingolipid metabolism is functionally linked to the proteolytic processing of APP. Results: Inhibition of S1P-lyase decreases APP degradation in lysosomes, and mobilization of Ca 2ϩ can partially rescue the accumulation of APP. Conclusion: S1P-lyase is critically involved in the regulation of lysosomal activity and degradation of APP. Significance: Alterations in S1P metabolism could play important roles in the pathogenesis of Alzheimer disease.

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Sphingosine 1-Phosphate (S1P) Lyase Deficiency Increases Sphingolipid Formation via Recycling at the Expense of de Novo Biosynthesis in Neurons

Cited by 47 publications

References 40 publications

Selective Absorption of Dietary Sphingoid Bases from the Intestine via Efflux by P-Glycoprotein in Rats

Selective Absorption of Dietary Sphingoid Bases from the Intestine via Efflux by P-Glycoprotein in Rats

Sphingosine-1-Phosphate: Boon and Bane for the Brain

Deficiency of Sphingosine-1-phosphate Lyase Impairs Lysosomal Metabolism of the Amyloid Precursor Protein

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