Second generation S1P pathway modulators: Research strategies and clinical developments

Bigaud, Marc; Guerini, Danilo; Billich, Andreas; Bassilana, Frédéric; Brinkmann, Volker

doi:10.1016/j.bbalip.2013.11.001

Cited by 114 publications

(122 citation statements)

References 184 publications

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“…However, the metabolism of 2-hydroxyhexadecanal is unclear and is the subject of this study. (b) [11, H]PHS prepared in this study and [4, ARTICLE When the pAN9 plasmid, which encoded the 3xFLAG-tagged DPL1 gene under the control of the GAPDH promoter, was introduced into the Ddpl1 cells, C15 and C17 PC levels increased greatly, even when compared with the wild-type control ( Supplementary Fig. 3).…”

Section: Resultsmentioning

confidence: 99%

“…The metabolism of PHS is currently unknown mainly due to the lack of commercially available radioactive PHS. Therefore, we prepared radiolabelled PHS ( [11, H]PHS) from [9, H]palmitic acid by metabolic conversion in yeast, followed by purification. The prepared [ 3 H]PHS presented as a single band that migrated to a position identical to a cold PHS standard on thin-layer chromatography (TLC; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Preparation of [11, H]PHS. BY4741 cells (100 ml) grown in YPD medium to log phase were labelled at 30°C for 4 h with 1 mCi [9,10-3 H]palmitic acid (40 Ci mmol À 1 , 10 mCi ml À 1 ; American Radiolabeled Chemical).…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, the sphingolipid metabolite sphingosine 1-phosphate (S1P) functions as a lipid mediator that regulates various cellular responses, such as egress of T cells from the thymus and secondary lymphoid tissues and vascular stabilization, by binding to one of the five S1P receptors (S1P 1-5 ) 6,10 . Its function in the immune system has already been applied clinically as a therapeutic agent for multiple sclerosis 11 .…”

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confidence: 99%

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Identification of the phytosphingosine metabolic pathway leading to odd-numbered fatty acids

et al. 2014

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The long-chain base phytosphingosine is a component of sphingolipids and exists in yeast, plants and some mammalian tissues. Phytosphingosine is unique in that it possesses an additional hydroxyl group compared with other long-chain bases. However, its metabolism is unknown. Here we show that phytosphingosine is metabolized to odd-numbered fatty acids and is incorporated into glycerophospholipids both in yeast and mammalian cells. Disruption of the yeast gene encoding long-chain base 1-phosphate lyase, which catalyzes the committed step in the metabolism of phytosphingosine to glycerophospholipids, causes an B40% reduction in the level of phosphatidylcholines that contain a C15 fatty acid. We also find that 2-hydroxypalmitic acid is an intermediate of the phytosphingosine metabolic pathway. Furthermore, we show that the yeast MPO1 gene, whose product belongs to a large, conserved protein family of unknown function, is involved in phytosphingosine metabolism. Our findings provide insights into fatty acid diversity and identify a pathway by which hydroxyl group-containing lipids are metabolized.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Identification of the phytosphingosine metabolic pathway leading to odd-numbered fatty acids

et al. 2014

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“…We therefore validated the therapeutic viability of targeting either signaling pathway, using medications that are either clinically available (ETN, an anti-TNF medication) or in clinical trials (S1P receptor antagonists) (19 Table 3). However, both interventions successfully reverse the STZ-augmented tone in HFD mice, normalizing it in both mesenteric and olfactory arteries to the level of ETN-or JTE013-treated NC controls (Fig.…”

Section: Hfd/stz Does Not Affect Pe Responses or Passive Diameters Inmentioning

confidence: 99%

Tumor Necrosis Factor/Sphingosine-1-Phosphate Signaling Augments Resistance Artery Myogenic Tone in Diabetes

et al. 2016

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Diabetes strongly associates with microvascular complications that ultimately promote multiorgan failure. Altered myogenic responsiveness compromises tissue perfusion, aggravates hypertension, and sets the stage for later permanent structural changes to the microcirculation. We demonstrate that skeletal muscle resistance arteries isolated from patients with diabetes have augmented myogenic tone, despite reasonable blood glucose control. To understand the mechanisms, we titrated a standard diabetes mouse model (high-fat diet plus streptozotocin [HFD/STZ]) to induce a mild increase in blood glucose levels. HFD/STZ treatment induced a progressive myogenic tone augmentation in mesenteric and olfactory cerebral arteries; neither HFD nor STZ alone had an effect on blood glucose or resistance artery myogenic tone. Using gene deletion models that eliminate tumor necrosis factor (TNF) or sphingosine kinase 1, we demonstrate that vascular smooth muscle cell TNF drives the elevation of myogenic tone via enhanced sphingosine-1-phosphate (S1P) signaling. Therapeutically antagonizing TNF (etanercept) or S1P (JTE013) signaling corrects this defect. Our investigation concludes that vascular smooth muscle cell TNF augments resistance artery myogenic vasoconstriction in a diabetes model that induces a small elevation of blood glucose. Our data demonstrate that microvascular reactivity is an early disease marker and advocate establishing therapies that strategically target the microcirculation.

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Sphingosine kinase 2 is essential for remyelination following cuprizone intoxication

Song

McEwen

Duncan

et al. 2021

Glia

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Therapeutics that promote oligodendrocyte survival and remyelination are needed to restore neurological function in demyelinating diseases. Sphingosine 1-phosphate (S1P) is an essential lipid metabolite that signals through five G-protein coupled receptors. S1P receptor agonists such as Fingolimod are valuable immunosuppressants used to treat multiple sclerosis, and promote oligodendrocyte survival. However, the role for endogenous S1P, synthesized by the enzyme sphingosine kinase 2 (SphK2), in oligodendrocyte survival and myelination has not been established. This study investigated the requirement for SphK2 in oligodendrocyte survival and remyelination using the cuprizone mouse model of acute demyelination, followed by spontaneous remyelination. Oligodendrocyte density did not differ between untreated wild-type (WT) and SphK2 knockout (SphK2 À/À ) mice. However, cuprizone treatment caused significantly greater loss of mature oligodendrocytes in SphK2 À/À compared to WT mice. Following cuprizone withdrawal, spontaneous remyelination occurred in WT but not SphK2 À/À mice, even though progenitor and mature oligodendrocyte density increased in both genotypes. Levels of cytotoxic sphingosine and ceramide were higher in the corpus callosum of SphK2 À/À mice, and in contrast to WT mice, did not decline following cuprizone withdrawal in SphK2 À/À mice. We also observed a significant reduction in myelin thickness with aging in SphK2 À/À compared to WT mice. These results provide the first evidence that SphK2, the dominant enzyme catalyzing S1P synthesis in the adult brain, is essential for remyelination following a demyelinating insult and myelin maintenance with aging. We propose that persistently high levels of sphingosine and ceramide, a direct consequence of SphK2 deficiency, may block remyelination.

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Second generation S1P pathway modulators: Research strategies and clinical developments

Cited by 114 publications

References 184 publications

Identification of the phytosphingosine metabolic pathway leading to odd-numbered fatty acids

Identification of the phytosphingosine metabolic pathway leading to odd-numbered fatty acids

Tumor Necrosis Factor/Sphingosine-1-Phosphate Signaling Augments Resistance Artery Myogenic Tone in Diabetes

Sphingosine kinase 2 is essential for remyelination following cuprizone intoxication

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