Sphingosine kinase and sphingosine-1-phosphate in liver pathobiology

Over 20 years ago, sphingosine-1-phosphate (S1P) was discovered to be a bioactive signaling molecule. Subsequent studies later identified two related kinases, sphingosine kinase 1 and 2, which are responsible for the phosphorylation of sphingosine to S1P. Many stimuli increase sphingosine kinase activity and S1P production and secretion. Outside the cell, S1P can bind to and activate five S1P-specific G protein-coupled receptors (S1PR1–5) to regulate many important cellular and physiological processes in an autocrine or paracrine manner. S1P is found in high concentrations in the blood where it functions to control vascular integrity and trafficking of lymphocytes. Obesity increases blood S1P levels in humans and mice. With the world wide increase in obesity linked to consumption of high-fat, high-sugar diets, S1P is emerging as an accomplice in liver pathobiology, including acute liver failure, metabolic syndrome, control of blood lipid and glucose homeostasis, nonalcoholic fatty liver disease, and liver fibrosis. Here, we review recent research on the importance of sphingosine kinases, S1P, and S1PRs in liver pathobiology, with a focus on exciting insights for new therapeutic modalities that target S1P signaling axes for a variety of liver diseases

Differential transactivation of sphingosine-1-phosphate receptors modulates NGF-induced neurite extension

The process of neurite extension after activation of the TrkA tyrosine kinase receptor by nerve growth factor (NGF) involves complex signaling pathways. Stimulation of sphingosine kinase 1 (SphK1), the enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P), is part of the functional TrkA signaling repertoire. In this paper, we report that in PC12 cells and dorsal root ganglion neurons, NGF translocates SphK1 to the plasma membrane and differentially activates the S1P receptors S1P1 and S1P2 in a SphK1-dependent manner, as determined with specific inhibitors and small interfering RNA targeted to SphK1. NGF-induced neurite extension was suppressed by down-regulation of S1P1 expression with antisense RNA. Conversely, when overexpressed in PC12 cells, transactivation of S1P1 by NGF markedly enhanced neurite extension and stimulation of the small GTPase Rac, important for the cytoskeletal changes required for neurite extension. Concomitantly, differentiation down-regulated expression of S1P2 whose activation would stimulate Rho and inhibit neurite extension. Thus, differential transactivation of S1P receptors by NGF regulates antagonistic signaling pathways that modulate neurite extension

Filamin a expression negatively regulates Sphingosine-1-phosphate-induced NF-κB activation in melanoma cells by inhibition o Akt signaling

Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that regulates many processes in inflammation and cancer. S1P is a ligand for five G-protein-coupled receptors, S1PR1 to -5, and also has important intracellular actions. Previously, we showed that intracellular S1P is involved in tumor necrosis factor alpha (TNF)-induced NF-κB activation in melanoma cell lines that express filamin A (FLNA). Here, we show that extracellular S1P activates NF-κB only in melanoma cells that lack FLNA. In these cells, S1P, but not TNF, promotes IκB kinase (IKK) and p65 phosphorylation, IκBα degradation, p65 nuclear translocation, and NF-κB reporter activity. NF-κB activation induced by S1P was mediated via S1PR1 and S1PR2. Exogenous S1P enhanced the phosphorylation of protein kinase Cδ (PKCδ), and its downregulation reduced S1P-induced the phosphorylation of IKK and p65. In addition, silencing of Bcl10 also inhibited S1P-induced IKK phosphorylation. Surprisingly, S1P reduced Akt activation in melanoma cells that express FLNA, whereas in the absence of FLNA, high phosphorylation levels of Akt were maintained, enabling S1P-mediated NF-κB signaling. In accord, inhibition of Akt suppressed S1P-mediated IKK and p65 phosphorylation and degradation of IκBα. Hence, these results support a negative role of FLNA in S1P-mediated NF-κB activation in melanoma cells through modulation of Akt.Fil: Campos, Ludmila Estefanía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Rodriguez, Yamila Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Machado Leopoldino, Andreia. Virginia Commonwealth University. School of Medicine; Estados Unidos. Universidade de Sao Paulo; BrasilFil: Hait, Nitai C.. Virginia Commonwealth University. School of Medicine; Estados UnidosFil: Lopez Bergami, Pablo Roberto. Universidad Maimonides; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Castro, Melina Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Sanchez, Emilse Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Maceyka, Michael. Virginia Commonwealth University. School of Medicine; Estados UnidosFil: Spiegel, Sarah. Virginia Commonwealth University School Of Medicine;Fil: Alvarez, Sergio Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; Argentin

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

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.Fil: Newton, Jason. Virginia Commonwealth University School of Medicine; Estados UnidosFil: Palladino, Elisa N.D.. Virginia Commonwealth University School of Medicine; Estados UnidosFil: Weigel, Cynthia. Virginia Commonwealth University School of Medicine; Estados UnidosFil: Maceyka, Michael. Virginia Commonwealth University School of Medicine; Estados UnidosFil: Gräler, Markus H.. Universitätsklinikum Jena; AlemaniaFil: Senkal, Can E.. Virginia Commonwealth University School of Medicine; Estados UnidosFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Marvanova, Pavlina. Veterinární univerzita Brno; República ChecaFil: Jampilek, Josef. Univerzita Komenského v Bratislave; EslovaquiaFil: Lima, Santiago. Virginia Commonwealth University; Estados UnidosFil: Milstien, Sheldon. Virginia Commonwealth University School of Medicine; Estados UnidosFil: Spiegel, Sarah. Virginia Commonwealth University School of Medicine; Estados Unido

Sphingosine kinases and their metabolites modulate endolysosomal trafficking in photoreceptors

Alterations in sphingosine kinase activity change the degradation rates of Rhodopsin and the transient receptor potential (TRP) channel by lysosomes and can result in retinal degeneration

PDMP Blocks Brefeldin A–induced Retrograde Membrane Transport from Golgi to ER: Evidence for Involvement of Calcium Homeostasis and Dissociation from Sphingolipid Metabolism

In this study, we show that an inhibitor of sphingolipid biosynthesis, d,l-threo-1-phenyl-2- decanoylamino-3-morpholino-1-propanol (PDMP), inhibits brefeldin A (BFA)-induced retrograde membrane transport from Golgi to endoplasmic reticulum (ER). If BFA treatment was combined with or preceded by PDMP administration to cells, disappearance of discrete Golgi structures did not occur. However, when BFA was allowed to exert its effect before PDMP addition, PDMP could not “rescue” the Golgi compartment

Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway

Apoptotic epithelial cells signal to neighboring cells to induce dying cell extrusion by releasing sphingosine-1-phosphate

Nutraceutical properties of chestnut flours: beneficial effects on skeletal muscle atrophy

Plants contain a wide range of non-nutritive phytochemicals, many of which have protective or preventive properties for human diseases. The aim of the present work has been to investigate the nutraceutical properties of sweet chestnut flour extracts obtained from fruits collected from 7 geographic areas of Tuscany (Italy), and their ability in modulating skeletal muscle atrophy. We found that the cultivars from different geographic areas are characterized by the composition and quantity of various nutrients and specific bioactive components, such as tocopherols, polyphenols and sphingolipids. The nutraceutical properties of chestnut sweet flours have been evaluated in C2C12 myotubes induced to atrophy by serum deprivation or dexamethasone. We found that the pretreatment with both total extracts of tocopherols and sphingolipids is able to counterbalance cell atrophy, reducing the decrease in myotube size and myonuclei number, and attenuating protein degradation and the increase in expression of MAFbx/atrogin-1 (a muscle-specific atrophy marker). By contrast, polyphenol extracts were not able to prevent atrophy. Since we also found that γ-tocopherol is the major form of tocopherol in sweet flour and its content differs depending on the procedure of sweet flour preparation, the mechanisms by which γ-tocopherol as well as sphingolipids affect skeletal muscle cell atrophy have been also investigated. This is the first evidence that chestnut sweet flour is a natural source of specific bioactive components with a relevant role in the prevention of cell degeneration and maintenance of skeletal muscle mass, opening important implications in designing appropriate nutritional therapeutic approaches to skeletal muscle atrophy

Sphingosine kinase A is a pleiotropic and essential enzyme for L eishmania survival and virulence

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100339/1/mmi12378.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/100339/2/mmi12378-sup-0001-si.pd