scholarly journals Feeding Stimulates Sphingosine-1-Phosphate Mobilization in Mouse Hypothalamus

2019 ◽  
Vol 20 (16) ◽  
pp. 4008
Author(s):  
Valentina Vozella ◽  
Natalia Realini ◽  
Alessandra Misto ◽  
Daniele Piomelli
Keyword(s):  
De Novo ◽  
Sphingolipid Metabolism ◽  
Rt Pcr ◽  
Liquid Chromatography Tandem Mass ◽  
Sphingosine 1 Phosphate ◽  
Phosphate Mobilization ◽  
S1p Receptor ◽  
Free Feeding ◽  
G Protein Coupled ◽  
Sphingolipid Biosynthesis

Previous studies have shown that the sphingolipid-derived mediator sphingosine-1-phosphate (S1P) reduces food intake by activating G protein-coupled S1P receptor-1 (S1PR1) in the hypothalamus. Here, we examined whether feeding regulates hypothalamic mobilization of S1P and other sphingolipid-derived messengers. We prepared lipid extracts from the hypothalamus of C57Bl6/J male mice subjected to one of four conditions: free feeding, 12 h fasting, and 1 h or 6 h refeeding. Liquid chromatography/tandem mass spectrometry was used to quantify various sphingolipid species, including sphinganine (SA), sphingosine (SO), and their bioactive derivatives SA-1-phosphate (SA1P) and S1P. In parallel experiments, transcription of S1PR1 (encoded in mice by the S1pr1 gene) and of key genes of sphingolipid metabolism (Sptlc2, Lass1, Sphk1, Sphk2) was measured by RT-PCR. Feeding increased levels of S1P (in pmol-mg−1 of wet tissue) and SA1P. This response was accompanied by parallel changes in SA and dihydroceramide (d18:0/18:0), and was partially (SA1P) or completely (S1P) reversed by fasting. No such effects were observed with other sphingolipid species targeted by our analysis. Feeding also increased transcription of Sptlc2, Lass1, Sphk2, and S1pr1. Feeding stimulates mobilization of endogenous S1PR1 agonists S1P and SA1P in mouse hypothalamus, via a mechanism that involves transcriptional up-regulation of de novo sphingolipid biosynthesis. The results support a role for sphingolipid-mediated signaling in the central control of energy balance.

scholarly journals Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain

2018 ◽  
Vol 215 (5) ◽  
pp. 1301-1313 ◽  
Author(s):  
Katherine Stockstill ◽  
Timothy M. Doyle ◽  
Xisheng Yan ◽  
Zhoumou Chen ◽  
Kali Janes ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
De Novo ◽  
Molecular Level ◽  
Spinal Cord Dorsal Horn ◽  
Sphingolipid Metabolism ◽  
Molecular Pathways ◽  
Sphingosine 1 Phosphate ◽  
Spinal Cord Dorsal ◽  
S1p Receptor ◽  
Insight Into

The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain. Mice with astrocyte-specific alterations of S1pr1 did not develop neuropathic pain and lost their ability to respond to S1PR1 inhibition, strongly implicating astrocytes as a primary cellular substrate for S1PR1 activity. At the molecular level, S1PR1 engaged astrocyte-driven neuroinflammation and altered glutamatergic homeostasis, processes blocked by S1PR1 antagonism. Our findings establish S1PR1 as a target for therapeutic intervention and provide insight into cellular and molecular pathways. As FTY720 also shows promising anticancer potential and is FDA approved, rapid clinical translation of our findings is anticipated.

Regulation of de novo sphingolipid biosynthesis and the toxic consequences of its disruption

2001 ◽  
Vol 29 (6) ◽  
pp. 831-835 ◽  
Author(s):  
S. C. Linn ◽  
H. S. Kim ◽  
E. M. Keane ◽  
L. M. Andras ◽  
E. Wang ◽  
...  
Keyword(s):  
De Novo ◽  
Uv Light ◽  
Wide Spectrum ◽  
Sphingolipid Metabolism ◽  
Intrinsic Activity ◽  
Type I ◽  
Serine Palmitoyltransferase ◽  
Post Translational Modification ◽  
Sphingolipid Biosynthesis ◽  
Complex Sphingolipids

Complex sphingolipids are ‘built’ on highly bio-active backbones (sphingoid bases and ceramides) that can cause cell death when the amounts are elevated by turnover of complex sphingolipids, disruption of normal sphingolipid metabolism, or over-induction of sphingolipid biosynthesis de novo. Under normal conditions, it appears that the bioactive intermediates of this pathway (3-keto-sphinganine, sphinganine and ceramides) are kept at relatively low levels. Both the intrinsic activity of serine palmitoyltransferase (SPT) and the availability of its substrates (especially palmitoyl-CoA) can have toxic consequences for cells by increasing the production of cytotoxic intermediates. Recent work has also revealed that diverse agonists and stresses (cytokines, UV light, glucocorticoids, heat shock and toxic compounds) modulate SPT activity by induction of SPTLC2 gene transcription and/or post-translational modification. Mutation of the SPTLC1 component of SPT has also been shown to cause hereditary sensory neuropathy type I, possibly via aberrant oversynthesis of sphingolipids. Another key step of the pathway is the acylation of sphinganine (and sphingosine in the recycling pathway) by ceramide synthase, and up-regulation of this enzyme (or its inhibition to cause accumulation of sphinganine) can also be toxic for cells. Since it appears that most, if not all, tissues synthesize sphingolipids de novo, it may not be surprising that disruption of this pathway has been implicated in a wide spectrum of disease.

scholarly journals S1P/S1P Receptor Signaling in Neuromuscolar Disorders

2019 ◽  
Vol 20 (24) ◽  
pp. 6364 ◽  
Author(s):  
Elisabetta Meacci ◽  
Mercedes Garcia-Gil
Keyword(s):  
Neuromuscular Diseases ◽  
Clinical Applications ◽  
G Protein Coupled Receptors ◽  
Receptor Signaling ◽  
Charcot Marie Tooth Disease ◽  
System Degeneration ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
G Protein Coupled ◽  
Tooth Disease

The bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), and the signaling pathways triggered by its binding to specific G protein-coupled receptors play a critical regulatory role in many pathophysiological processes, including skeletal muscle and nervous system degeneration. The signaling transduced by S1P binding appears to be much more complex than previously thought, with important implications for clinical applications and for personalized medicine. In particular, the understanding of S1P/S1P receptor signaling functions in specific compartmentalized locations of the cell is worthy of being better investigated, because in various circumstances it might be crucial for the development or/and the progression of neuromuscular diseases, such as Charcot–Marie–Tooth disease, myasthenia gravis, and Duchenne muscular dystrophy.

scholarly journals Resveratrol Targets Sphingolipid Metabolism to Induce Growth Inhibition in FLT3 ITD Acute Myeloid Leukemia

Proceedings ◽  
2019 ◽  
Vol 40 (1) ◽  
pp. 4
Author(s):  
Ersöz ◽  
Adan
Keyword(s):  
Growth Inhibition ◽  
Cell Fate ◽  
De Novo ◽  
Therapeutic Potential ◽  
Annexin V ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Cytotoxic Effects ◽  
Sphingosine 1 Phosphate ◽  
First Time

Sphingolipids are important signaling lipids which play crucial roles to determine the cell fate. Ceramide, apoptotic central molecule of sphingolipid metabolism, which is produced through de novo pathway by serine palmitoyl transferase (SPT) and can be converted to antiapoptotic sphingosine-1-phosphate (S1P) and glucosyl ceramide (GC) by sphingosine kinase (SK) and glucosyl ceramide synthase (GCS), respectively. It is aimed to investigate therapeutic potential of resveratrol on FLT3-ITD (Internal Tandem Duplication) AML cells and to identify potential mechanism behind resveratrol-mediated growth inhibition by targeting of ceramide metabolism. The cytotoxic effects of resveratrol, SPT inhibitor (myricoin), SK-1 inhibitor (SKI II), GCS inhibitor (PDMP), resveratrol: SPT inhibitor, resveratrol: SK-1 inhibitor and resveratrol: GCS inhibitor combinations on MOLM-13 and MV4-11 FLT3 ITD AML cells were investigated by cell proliferation assay. Apoptosis was evaluated by annexin V/PI double staining. There were synergistic cytotoxic effects of resveratrol with co-administration of SPT inhibitor, SK-1 inhibitor and GCS inhibitor and apoptosis was synergistically induced for resveratrol and its combinations. This preliminary data showed for the first time that resveratrol might inhibit the growth of FLT3 ITD AML cells through targeting ceramide metabolism.

The effect of altered sphingolipid acyl chain length on various disease models

2015 ◽  
Vol 396 (6-7) ◽  
pp. 693-705 ◽  
Author(s):  
Woo-Jae Park ◽  
Joo-Won Park
Keyword(s):  
Chain Length ◽  
De Novo ◽  
Case Reports ◽  
Acyl Chain ◽  
Fatty Acyl ◽  
Sphingolipid Metabolism ◽  
Lipid Mediator ◽  
Disease Models ◽  
Acyl Chain Length ◽  
Sphingosine 1 Phosphate

Abstract Sphingolipids have emerged as an important lipid mediator in intracellular signalling and metabolism. Ceramide, which is central to sphingolipid metabolism, is generated either via a de novo pathway, by attaching fatty acyl CoA to a long-chain base, or via a salvage pathway, by degrading pre-existing sphingolipids. As a ‘sphingolipid rheostat’ has been proposed, the balance between ceramide and sphingosine-1-phosphate has been the object of considerable attention. Ceramide has recently been reported to have a different function depending on its acyl chain length: six ceramide synthases (CerS) determine the specific ceramide acyl chain length in mammals. All CerS-deficient mice generated to date show that sphingolipids with defined acyl chain lengths play distinct pathophysiological roles in disease models. This review describes recent advances in understanding the associations of CerS with various diseases and includes clinical case reports.

scholarly journals Sphingosine-1-phosphate receptor subtype 1 activation in the central nervous system contributes to morphine withdrawal in rodents

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Timothy M. Doyle ◽  
Mark R. Hutchinson ◽  
Kathryn Braden ◽  
Kali Janes ◽  
Vicky Staikopoulos ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Side Effects ◽  
De Novo ◽  
Morphine Withdrawal ◽  
Sphingolipid Metabolism ◽  
Receptor Subtype ◽  
Precipitated Withdrawal ◽  
Sphingosine 1 Phosphate ◽  
Withdrawal Behaviors ◽  
The Impact

Abstract Opioid therapies for chronic pain are undermined by many adverse side effects that reduce their efficacy and lead to dependence, abuse, reduced quality of life, and even death. We have recently reported that sphingosine-1-phosphate (S1P) 1 receptor (S1PR1) antagonists block the development of morphine-induced hyperalgesia and analgesic tolerance. However, the impact of S1PR1 antagonists on other undesirable side effects of opioids, such as opioid-induced dependence, remains unknown. Here, we demonstrate that naloxone-precipitated morphine withdrawal in mice altered de novo sphingolipid metabolism in the dorsal horn of the spinal cord and increased S1P that accompanied the manifestation of several withdrawal behaviors. Blocking de novo sphingolipid metabolism with intrathecal administration of myriocin, an inhibitor of serine palmitoyltransferase, blocked naloxone-precipitated withdrawal. Noteworthy, we found that competitive (NIBR-15) and functional (FTY720) S1PR1 antagonists attenuated withdrawal behaviors in mice. Mechanistically, at the level of the spinal cord, naloxone-precipitated withdrawal was associated with increased glial activity and formation of the potent inflammatory/neuroexcitatory cytokine interleukin-1β (IL-1β); these events were attenuated by S1PR1 antagonists. These results provide the first molecular insight for the role of the S1P/S1PR1 axis during opioid withdrawal. Our data identify S1PR1 antagonists as potential therapeutics to mitigate opioid-induced dependence and support repurposing the S1PR1 functional antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct.

scholarly journals Differential Expression of Sphingolipid Metabolizing Enzymes in Spontaneously Hypertensive Rats: A Possible Substrate for Susceptibility to Brain and Kidney Damage

2021 ◽  
Vol 22 (7) ◽  
pp. 3796
Author(s):  
Giuseppe Pepe ◽  
Maria Cotugno ◽  
Federico Marracino ◽  
Susy Giova ◽  
Luca Capocci ◽  
...  
Keyword(s):  
De Novo ◽  
Spontaneously Hypertensive Rat ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Biologically Active ◽  
Sphingolipid Metabolism ◽  
Spontaneously Hypertensive ◽  
Sphingosine 1 Phosphate ◽  
Rat Strain ◽  
Wistar Kyoto

Alterations in the metabolism of sphingolipids, a class of biologically active molecules in cell membranes with direct effect on vascular homeostasis, are increasingly recognized as important determinant in different vascular disorders. However, it is not clear whether sphingolipids are implicated in the pathogenesis of hypertension-related cerebrovascular and renal damage. In this study, we evaluated the existence of possible abnormalities related to the sphingolipid metabolism in the brain and kidneys of two well validated spontaneously hypertensive rat strains, the stroke-prone (SHRSP) and the stroke-resistant (SHRSR) models, as compared to the normotensive Wistar Kyoto (WKY) rat strain. Our results showed a global alteration in the metabolism of sphingolipids in both cerebral and renal tissues of both hypertensive strains as compared to the normotensive rat. However, few defects, such as reduced expression of enzymes involved in the metabolism/catabolism of sphingosine-1-phosphate and in the de novo biosynthetic pathways, were exclusively detected in the SHRSP. Although further studies are necessary to fully understand the significance of these findings, they suggest that defects in specific lipid molecules and/or their related metabolic pathways may likely contribute to the pathogenesis of hypertensive target organ damage and may eventually serve as future therapeutic targets to reduce the vascular consequences of hypertension.

scholarly journals Signal Transduction of Sphingosine-1-Phosphate G Protein—Coupled Receptors

2006 ◽  
Vol 6 ◽  
pp. 946-966 ◽  
Author(s):  
Nicholas Young ◽  
James R. Van Brocklyn
Keyword(s):  
Signal Transduction ◽  
G Protein ◽  
Cell Types ◽  
G Protein Coupled Receptors ◽  
Lymphocyte Trafficking ◽  
Cytoskeletal Organization ◽  
Cellular Effects ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
G Protein Coupled

Sphingosine-1-phosphate (S1P) is a bioactive lipid capable of eliciting dramatic effects in a variety of cell types. Signaling by this molecule is by a family of five G protein—coupled receptors named S1P1–5that signal through a variety of pathways to regulate cell proliferation, migration, cytoskeletal organization, and differentiation. These receptors are expressed in a wide variety of tissues and cell types, and their cellular effects contribute to important biological and pathological functions of S1P in many processes, including angiogenesis, vascular development, lymphocyte trafficking, and cancer. This review will focus on the current progress in the field of S1P receptor signaling and biology.

scholarly journals Sphingosine-1-phosphate receptor subtype-specific positive and negative regulation of Rac and haematogenous metastasis of melanoma cells

2003 ◽  
Vol 374 (3) ◽  
pp. 715-722 ◽  
Author(s):  
Hironori YAMAGUCHI ◽  
Joji KITAYAMA ◽  
Noriko TAKUWA ◽  
Kayo ARIKAWA ◽  
Isao INOKI ◽  
...  
Keyword(s):  
Cell Migration ◽  
G Protein ◽  
Lung Metastasis ◽  
Melanoma Cells ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
G Protein Coupled ◽  
Stimulation Of

We have recently reported that S1P (sphingosine-1-phosphate) differentially regulates cellular Rac activity and cell migration in either a positive or a negative direction via distinct G-protein-coupled receptor subtypes, i.e. S1P1/Edg1 (endothelial differentiation gene) and S1P2/Edg5 respectively, when each of the S1P receptor subtypes is expressed in CHO (Chinese-hamster ovary) cells. In B16F10 mouse melanoma cells, in which S1P2, but not the other S1P receptor subtypes, is endogenously expressed, S1P inhibited cell migration with concomitant inhibition of Rac and stimulation of RhoA in dose-dependent manners. Overexpression of S1P2 in the melanoma cells resulted in potentiation of S1P inhibition of both Rac and cell migration. In contrast, overexpression of S1P1 led to stimulation of cell migration, particularly at the lower S1P concentrations. Treatment of B16F10 cells with S1P inhibited lung metastasis 3 weeks after injection into mouse tail veins. Intriguingly, overexpression of S1P2 greatly potentiated the inhibition of metastasis by S1P, whereas that of S1P1 resulted in aggravation of metastasis. Suppression of cellular Rac activity by adenovirus-transduced expression of N17Rac, but not N19RhoA, strongly inhibited cell migration in vitro and lung metastasis in vivo. These results provide the first evidence that G-protein-coupled receptors could participate in the regulation of metastasis, in which ligand-dependent, subtype-specific regulation of the cellular Rac activity is probably critically involved as a mechanism.

scholarly journals The concept of sphingolipid rheostat in skin: a driving force for new active ingredients in cosmetic applications

OCL ◽  
2018 ◽  
Vol 25 (5) ◽  
pp. D507 ◽  
Author(s):  
Iuliana Popa
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Stratum Corneum ◽  
Driving Force ◽  
Mammalian Cells ◽  
De Novo ◽  
Oral Treatment ◽  
Sphingolipid Metabolism ◽  
Intercellular Signaling ◽  
Sphingosine 1 Phosphate

Skin is a representative model of the complex metabolism that lipids may trigger. It is known that the biosynthesis of these lipids in mammalian cells generally ensures the cell membranes stability and participates to the signaling function. In the inner layers of the skin, the “de-novo” synthesis is the driving force ensuring proliferation, development and intercellular signaling. To promote stratum corneum formation, lipid catabolism leads to the renewal of ceramides, fatty acids and cholesterol that are responsible for the cohesion of the stratum corneum, its permeability, hydration, moisturization and signalling with the outer skin layers, appendages and inner layers secretion (cytokines, neuropeptides). Some actives applied in local treatments (i.e., peptides, n-3 polyunsaturated fatty acids (PUFA), ceramides, urea or an aqueous extract of Gromwell) and in oral treatment (i.e., sphingomyelin, n-3 polyunsaturated fatty acids (PUFA)) promote sphingosine 1-phosphate (S1P) production by the sphingolipid rheostat via triggering the salvage process along with autophagy and detoxification in aged skin. This review gives some basis for using the concept of sphingolipid metabolism rheostat in skin as the driving force for the development of new cosmetic actives ingredients or for repositioning the benefits of other actives for the skin.

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