Intergenerational Neuroprotection by an Intestinal Sphingolipid in Caenorhabditis elegans
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ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE214425 | GEO | 2023/06/26
REPOSITORIES: GEO
Similar Datasets
Project description:Intergenerational Neuroprotection by an Intestinal Sphingolipid in Caenorhabditis elegans
| PRJNA885375 | ENA
Project description:The cleavage of sphingoid base phosphates by sphingosine-1-phosphate (S1P) lyase to produce phosphoethanolamine and a fatty aldehyde is the final degradative step in the sphingolipid metabolic pathway. We have studied mice with an inactive S1P lyase gene and have found that, in addition to the expected increase of sphingoid base phosphates, other sphingolipids (including sphingosine, ceramide, and sphingomyelin) were substantially elevated in the serum and /or liver of these mice. This latter increase is consistent with a reutilization of the sphingosine backbone for sphingolipid synthesis due to its inability to exit the sphingolipid metabolic pathway. Furthermore, the S1P lyase deficiency resulted in changes in the levels of serum and liver lipids not directly within the sphingolipid pathway, including phospholipids, triacyglycerol, diacylglycerol, and cholesterol. Even though lipids in serum and lipid storage were elevated in liver, adiposity was reduced in the S1P lyase-deficient mice. Microarray analysis of lipid metabolism genes in liver showed that the S1P lyase deficiency caused widespread changes in their expression pattern. These results demonstrate that S1P lyase is a key regulator of the levels of multiple sphingolipid substrates and reveal functional links between the sphingolipid metabolic pathway and other lipid metabolic pathways that may be mediated by shared lipid substrates and changes in gene expression programs. The disturbance of lipid homeostasis by altered sphingolipid levels may be relevant to metabolic diseases. Experiment Overall Design: RNA samples from liver for three sphingosine-1-phosphate lyase knock-out and three WT mice.
2010-02-05 | E-GEOD-18745 | biostudies-arrayexpress
Project description:The cleavage of sphingoid base phosphates by sphingosine-1-phosphate (S1P) lyase to produce phosphoethanolamine and a fatty aldehyde is the final degradative step in the sphingolipid metabolic pathway. We have studied mice with an inactive S1P lyase gene and have found that, in addition to the expected increase of sphingoid base phosphates, other sphingolipids (including sphingosine, ceramide, and sphingomyelin) were substantially elevated in the serum and /or liver of these mice. This latter increase is consistent with a reutilization of the sphingosine backbone for sphingolipid synthesis due to its inability to exit the sphingolipid metabolic pathway. Furthermore, the S1P lyase deficiency resulted in changes in the levels of serum and liver lipids not directly within the sphingolipid pathway, including phospholipids, triacyglycerol, diacylglycerol, and cholesterol. Even though lipids in serum and lipid storage were elevated in liver, adiposity was reduced in the S1P lyase-deficient mice. Microarray analysis of lipid metabolism genes in liver showed that the S1P lyase deficiency caused widespread changes in their expression pattern. These results demonstrate that S1P lyase is a key regulator of the levels of multiple sphingolipid substrates and reveal functional links between the sphingolipid metabolic pathway and other lipid metabolic pathways that may be mediated by shared lipid substrates and changes in gene expression programs. The disturbance of lipid homeostasis by altered sphingolipid levels may be relevant to metabolic diseases.
2010-01-28 | GSE18745 | GEO
Project description:To investigate the effect of the sphingolipid S1P secreted by melanoma cells on epidermal keratinocytes, we treated human primary keratinocytes with exogenous S1P.
2023-12-18 | GSE230050 | GEO
Project description:Mothers contribute cytoplasmic components to their progeny in a process called maternal provisioning. Provisioning is influenced by the parental environment, but the molecular pathways that transmit environmental cues between generations are not well understood. Here we show that in C. elegans, social cues modulate maternal provisioning to regulate gene silencing in offspring. Intergenerational signal transmission depends on a pheromone-sensing neuron and neuronal FMRFamide (Phe-Met-Arg-Phe)-like peptides. Parental FMRFamide-like peptide signaling dampens oxidative stress resistance and promotes the deposition of mRNAs for translational components in progeny, which in turn reduces gene silencing. This study identifies a new pathway for intergenerational communication that links neuronal responses to maternal provisioning. We suggest that loss of social cues in the parental environment represents an adverse environment that stimulates stress responses across generations.
2021-05-19 | GSE174646 | GEO
Project description:Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite that regulates basic cell functions through metabolic and signaling pathways. Intracellular metabolism of S1P is controlled, in part, by two homologous S1P phosphatases, 1 and 2, which are encoded by Sgpp1 and Sgpp2, respectively. S1P phosphatase activity is needed for efficient recycling of sphingosine into the sphingolipid synthesis pathway. S1P phosphatase 1 is important for skin homeostasis, but little is known about the functional role of S1P phosphatase 2. To identify the functions of S1P phosphatase 2 in vivo, we studied mice with the Sgpp2 gene deleted. In contrast to Sgpp1-/- mice, Sgpp2-/- mice had normal skin and were viable into adulthood. Unexpectedly, WT mice expressed Sgpp2 mRNA at high levels in pancreatic islets when compared with other tissues. Sgpp2-/- mice had normal blood insulin levels and pancreatic islet size; however, Sgpp2-/- mice treated with a high-fat diet (HFD) had significantly lower blood insulin levels and smaller pancreatic islets compared with WT mice. The smaller islets in the HFD-treated Sgpp2-/- mice had a significantly lower adaptive B-cell proliferation rate in response to the diet compared with HFD-treated WT mice. Importantly, B-cells from Sgpp2-/- mice fed a normal diet showed significantly increased expression of proteins characteristic of the endoplasmic reticulum (ER) stress response compared with B-cells from WT mice. Our results suggest that Sgpp2 deletion causes B-cell ER stress, which is a known cause of B-cell dysfunction, and reveal a novel juncture in the sphingolipid recycling pathway that could impact the development of diabetes. Three replications of Mouse (WT vs KO) that were treated with with Normal and HFD foods.
2016-07-25 | E-GEOD-73131 | biostudies-arrayexpress
Project description:Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite that regulates basic cell functions through metabolic and signaling pathways. Intracellular metabolism of S1P is controlled, in part, by two homologous S1P phosphatases, 1 and 2, which are encoded by Sgpp1 and Sgpp2, respectively. S1P phosphatase activity is needed for efficient recycling of sphingosine into the sphingolipid synthesis pathway. S1P phosphatase 1 is important for skin homeostasis, but little is known about the functional role of S1P phosphatase 2. To identify the functions of S1P phosphatase 2 in vivo, we studied mice with the Sgpp2 gene deleted. In contrast to Sgpp1-/- mice, Sgpp2-/- mice had normal skin and were viable into adulthood. Unexpectedly, WT mice expressed Sgpp2 mRNA at high levels in pancreatic islets when compared with other tissues. Sgpp2-/- mice had normal blood insulin levels and pancreatic islet size; however, Sgpp2-/- mice treated with a high-fat diet (HFD) had significantly lower blood insulin levels and smaller pancreatic islets compared with WT mice. The smaller islets in the HFD-treated Sgpp2-/- mice had a significantly lower adaptive β-cell proliferation rate in response to the diet compared with HFD-treated WT mice. Importantly, β-cells from Sgpp2-/- mice fed a normal diet showed significantly increased expression of proteins characteristic of the endoplasmic reticulum (ER) stress response compared with β-cells from WT mice. Our results suggest that Sgpp2 deletion causes β-cell ER stress, which is a known cause of β-cell dysfunction, and reveal a novel juncture in the sphingolipid recycling pathway that could impact the development of diabetes.
2016-07-25 | GSE73131 | GEO
Project description:Clinically significant radiation-induced lung injury (RILI) is associated with significant morbidity and mortality and a common toxicity in patients administered thoracic radiotherapy. While the molecular etiology of RILI is poorly understood, we previously characterized a murine model of RILI in which alterations in lung endothelial barrier integrity surfaced as a potentially important pathobiologic event. In these studies, inhibition of HMG-CoA reductase activity (simvastatin) reduced murine RILI-associated lung inflammation and vascular leak and attenuated radiation-induced dysregulation of sphingolipid metabolic pathway genes identified by genome-wide lung gene expression profiling. In the present study, we test the hypothesis that sphingolipid signaling components serve as important modulators of RILI pathobiology and novel therapeutic targets. Sphingolipid involvement in murine RILI was confirmed by radiation-induced increases in lung expression of sphingosine kinase (SphK) isoforms 1 and 2 and increases in the ratio of ceramide to cumulative sphingosine-1-phosphate (S1P) and dihydro-S1P (DHS1P) levels in plasma, bronchoalveolar lavage (BAL) fluid and lung tissue following 25 Gy exposure (6 weeks). Moreover, genetically-engineered mice with either targeted deletion of SphK1 (SphK1-/-), or with reduced expression of selective members of the S1P receptor family (S1PR1+/-, S1PR2-/-, S1PR3-/-,), exhibited marked susceptibility to RILI-mediated lung inflammation. Finally, we assessed the efficacy of three potent vascular barrier-protective S1P analogues FTY720 (FTY), fTysiponate (fTyS) and SEW-2871 (SEW) in attenuating indices of RILI. The phosphonate analogue, fTyS, and to a lesser degree SEW, exhibited significant attenuation of RILI and RILI-induced gene dysregulation compared to control RILI-challenged mice (6 weeks). In contrast, FTY failed to significantly alter physiologic or genomic changes compared to RILI-challenged controls. Together, these results support the targeting of sphingolipid components as a novel and effective therapeutic strategy in RILI. Four mice were treated with PBS as a control. Three mice were treated with (S)-FTY-phosphonate (0.1mg/kg) as a drug control. Three mice were treated with SEW-2871 (0.1mg/kg) as a drug control. Three mice were treated with FTY720 (0.1mg/kg) as a drug control. Three mice were treated with administered radiation (25 Gy) alone. Three mice were treated with both administered radiation (25 Gy) and (S)-FTY-phosphonate (0.1mg/kg). Three mice were treated with both administered radiation (25 Gy) and SEW-2871 (0.1mg/kg). Three mice were treated with both administered radiation (25 Gy) and FTY720 (0.1mg/kg).
2010-11-17 | E-GEOD-25295 | biostudies-arrayexpress
Project description:Utilization of lipids as energy substrates after birth causes cardiomyocyte (CM) cell-cycle arrest and loss of regenerative capacity in mammalian hearts. Beyond energy provision, proper management of lipid composition is crucial for cellular and organismal health, but its role in heart regeneration remains unclear. Here, we demonstrate widespread sphingolipid metabolism remodeling in neonatal hearts after injury and find that SphK1 and SphK2, isoenzymes producing the same sphingolipid metabolite sphingosine-1-phosphate (S1P), differently regulate cardiac regeneration. SphK2 is downregulated during heart development and determines CM proliferation via nuclear S1P-dependent modulation of histone acetylation. Reactivation of SphK2 induces adult CM cell-cycle re-entry and cytokinesis, thereby enhancing regeneration. Conversely, SphK1 is upregulated during development and promotes fibrosis through an S1P autocrine mechanism in cardiac fibroblasts. By fine-tuning the activity of each SphK isoform, we develop a therapy that simultaneously promotes myocardial repair and restricts fibrotic scarring to regenerate the infarcted adult hearts.
2024-06-04 | GSE180249 | GEO
Project description:Clinically significant radiation-induced lung injury (RILI) is associated with significant morbidity and mortality and a common toxicity in patients administered thoracic radiotherapy. While the molecular etiology of RILI is poorly understood, we previously characterized a murine model of RILI in which alterations in lung endothelial barrier integrity surfaced as a potentially important pathobiologic event. In these studies, inhibition of HMG-CoA reductase activity (simvastatin) reduced murine RILI-associated lung inflammation and vascular leak and attenuated radiation-induced dysregulation of sphingolipid metabolic pathway genes identified by genome-wide lung gene expression profiling. In the present study, we test the hypothesis that sphingolipid signaling components serve as important modulators of RILI pathobiology and novel therapeutic targets. Sphingolipid involvement in murine RILI was confirmed by radiation-induced increases in lung expression of sphingosine kinase (SphK) isoforms 1 and 2 and increases in the ratio of ceramide to cumulative sphingosine-1-phosphate (S1P) and dihydro-S1P (DHS1P) levels in plasma, bronchoalveolar lavage (BAL) fluid and lung tissue following 25 Gy exposure (6 weeks). Moreover, genetically-engineered mice with either targeted deletion of SphK1 (SphK1-/-), or with reduced expression of selective members of the S1P receptor family (S1PR1+/-, S1PR2-/-, S1PR3-/-,), exhibited marked susceptibility to RILI-mediated lung inflammation. Finally, we assessed the efficacy of three potent vascular barrier-protective S1P analogues FTY720 (FTY), fTysiponate (fTyS) and SEW-2871 (SEW) in attenuating indices of RILI. The phosphonate analogue, fTyS, and to a lesser degree SEW, exhibited significant attenuation of RILI and RILI-induced gene dysregulation compared to control RILI-challenged mice (6 weeks). In contrast, FTY failed to significantly alter physiologic or genomic changes compared to RILI-challenged controls. Together, these results support the targeting of sphingolipid components as a novel and effective therapeutic strategy in RILI.
2010-11-17 | GSE25295 | GEO