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Article ; Online: Special Section on Therapeutic Implications for Sphingolipids in Health and Disease-Editorial.

Clarke, Christopher J / Snider, Ashley J

2024 Volume 105, Issue 3, Page(s) 116–117

MeSH term(s)	Sphingolipids ; Signal Transduction
Chemical Substances	Sphingolipids
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Editorial
ZDB-ID	124034-1
ISSN	1521-0111 ; 0026-895X
ISSN (online)	1521-0111
ISSN	0026-895X
DOI	10.1124/molpharm.124.000863
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Article ; Online: Perspective: Therapeutic Implications for Sphingolipids in Health and Disease.

Clarke, Christopher J / Snider, Ashley J

Molecular pharmacology

2024 Volume 105, Issue 3, Page(s) 118–120

Abstract: Long thought to be structural components of cell membranes, sphingolipids (SLs) have emerged as bioactive molecules whose metabolism is tightly regulated. These bioactive lipids and their metabolic enzymes have been implicated in numerous disease states, ...

Abstract	Long thought to be structural components of cell membranes, sphingolipids (SLs) have emerged as bioactive molecules whose metabolism is tightly regulated. These bioactive lipids and their metabolic enzymes have been implicated in numerous disease states, including lysosomal storage disorders, multiple sclerosis, inflammation, and cancer as well as metabolic syndrome and obesity. In addition, the indications for many of these lipids to potentially serve as biomarkers for disease continue to emerge with increasing metabolomic and lipidomic studies. The implications of these studies have, in turn, led to the examination of SL enzymes and their bioactive lipids as potential therapeutic targets and as markers for therapeutic efficacy. SIGNIFICANCE STATEMENT: Many sphingolipids (SLs) and their metabolizing enzymes have been implicated in disease. This perspective highlights the potential for SLs to serve as therapeutic targets and diagnostic markers and discusses the implications for the studies and reviews highlighted in this Special Section on Therapeutic Implications for Sphingolipids in Health and Disease.
MeSH term(s)	Humans ; Sphingolipids/chemistry ; Sphingolipids/metabolism ; Neoplasms/therapy ; Obesity ; Cell Membrane/metabolism
Chemical Substances	Sphingolipids
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	124034-1
ISSN	1521-0111 ; 0026-895X
ISSN (online)	1521-0111
ISSN	0026-895X
DOI	10.1124/molpharm.124.000866
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Article: Therapeutic Potential for Sphingolipids in Inflammatory Bowel Disease and Colorectal Cancer.

Espinoza, Keila S / Snider, Ashley J

Cancers

2024 Volume 16, Issue 4

Abstract: Inflammatory bowel disease (IBD), characterized by chronic inflammation in the intestinal tract, increases the risk for the development of colorectal cancer (CRC). Sphingolipids, which have been implicated in IBD and CRC, are a class of bioactive lipids ... ...

Abstract	Inflammatory bowel disease (IBD), characterized by chronic inflammation in the intestinal tract, increases the risk for the development of colorectal cancer (CRC). Sphingolipids, which have been implicated in IBD and CRC, are a class of bioactive lipids that regulate cell signaling, differentiation, apoptosis, inflammation, and survival. The balance between ceramide (Cer), the central sphingolipid involved in apoptosis and differentiation, and sphingosine-1-phosphate (S1P), a potent signaling molecule involved in proliferation and inflammation, is vital for the maintenance of normal cellular function. Altered sphingolipid metabolism has been implicated in IBD and CRC, with many studies highlighting the importance of S1P in inflammatory signaling and pro-survival pathways. A myriad of sphingolipid analogues, inhibitors, and modulators have been developed to target the sphingolipid metabolic pathway. In this review, the efficacy and therapeutic potential for modulation of sphingolipid metabolism in IBD and CRC will be discussed.
Language	English
Publishing date	2024-02-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers16040789
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Article: Diet, lipids and colon cancer.

Choi, Songhwa / Snider, Ashley J

International review of cell and molecular biology

2019 Volume 347, Page(s) 105–144

Abstract: Dietary fat is digested and absorbed in the small intestine and can then be utilized as an energy source and/or as a reservoir for other bioactive lipid species. Excessive dietary fat has been implicated in the induction and/or aggravation of several ... ...

Abstract	Dietary fat is digested and absorbed in the small intestine and can then be utilized as an energy source and/or as a reservoir for other bioactive lipid species. Excessive dietary fat has been implicated in the induction and/or aggravation of several diseases, including colorectal cancer (CRC). Diets with high fat content have been shown to exacerbate CRC through regulation of intestinal inflammation and proliferation, as well as alteration of bile acid pools, microbiota, and bioactive lipid species. This chapter will investigate the effects of dietary fat on CRC development and pathobiology, and possible mechanisms for specific lipid species in those processes.
MeSH term(s)	Animals ; Bile Acids and Salts/adverse effects ; Bile Acids and Salts/immunology ; Bile Acids and Salts/metabolism ; Colitis, Ulcerative/complications ; Colon/immunology ; Colon/metabolism ; Colon/microbiology ; Colon/pathology ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/etiology ; Colorectal Neoplasms/metabolism ; Crohn Disease/complications ; Diet, High-Fat/adverse effects ; Dietary Fats/adverse effects ; Dietary Fats/metabolism ; Gastrointestinal Microbiome ; Humans ; Inflammation/metabolism ; Lipid Metabolism
Chemical Substances	Bile Acids and Salts ; Dietary Fats
Language	English
Publishing date	2019-07-29
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2427220-6
ISSN	1937-6448 ; 0074-7696
ISSN	1937-6448 ; 0074-7696
DOI	10.1016/bs.ircmb.2019.07.001
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Article ; Online: Expression of Ceramide Synthases in Mice and Their Roles in Regulating Acyl-Chain Sphingolipids: A Framework for Baseline Levels and Future Implications in Aging and Disease.

Richardson, Whitney J / Humphrey, Sophia B / Sears, Sophia M / Hoffman, Nicholas A / Orwick, Andrew J / Doll, Mark A / Doll, Chelsea L / Xia, Catherine / Hernandez-Corbacho, Maria / Snider, Justin M / Obeid, Lina M / Hannun, Yusuf A / Snider, Ashley J / Siskind, Leah J

Molecular pharmacology

2024 Volume 105, Issue 3, Page(s) 131–143

Abstract: Sphingolipids are an important class of lipids present in all eukaryotic cells that regulate critical cellular processes. Disturbances in sphingolipid homeostasis have been linked to several diseases in humans. Ceramides are central in sphingolipid ... ...

Abstract	Sphingolipids are an important class of lipids present in all eukaryotic cells that regulate critical cellular processes. Disturbances in sphingolipid homeostasis have been linked to several diseases in humans. Ceramides are central in sphingolipid metabolism and are largely synthesized by six ceramide synthase (CerS) isoforms (CerS1-6), each with a preference for different fatty acyl chain lengths. Although the tissue distribution of CerS mRNA expression in humans and the roles of CerS isoforms in synthesizing ceramides with different acyl chain lengths are known, it is unknown how CerS expression dictates ceramides and downstream metabolites within tissues. In this study, we analyzed sphingolipid levels and CerS mRNA expression in 3-month-old C57BL/6J mouse brain, heart, kidney, liver, lung, and skeletal muscle. The results showed that CerS expression and sphingolipid species abundance varied by tissue and that CerS expression was a predictor of ceramide species within tissues. Interestingly, although CerS expression was not predictive of complex sphingolipid species within all tissues, composite scores for CerSs contributions to total sphingolipids measured in each tissue correlated to CerS expression. Lastly, we determined that the most abundant ceramide species in mouse tissues aligned with CerS mRNA expression in corresponding human tissues (based on chain length preference), suggesting that mice are relevant preclinical models for ceramide and sphingolipid research. SIGNIFICANCE STATEMENT: The current study demonstrates that ceramide synthase (CerS) expression in specific tissues correlates not only with ceramide species but contributes to the generation of complex sphingolipids as well. As many of the CerSs and/or specific ceramide species have been implicated in disease, these studies suggest the potential for CerSs as therapeutic targets and the use of sphingolipid species as diagnostics in specific tissues.
MeSH term(s)	Mice ; Animals ; Humans ; Infant ; Sphingolipids/genetics ; Sphingolipids/metabolism ; Mice, Inbred C57BL ; Ceramides/genetics ; Ceramides/metabolism ; Protein Isoforms ; Aging/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Oxidoreductases
Chemical Substances	Sphingolipids ; dihydroceramide desaturase (EC 1.3.1.-) ; Ceramides ; Protein Isoforms ; RNA, Messenger ; Oxidoreductases (EC 1.-)
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	124034-1
ISSN	1521-0111 ; 0026-895X
ISSN (online)	1521-0111
ISSN	0026-895X
DOI	10.1124/molpharm.123.000788
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Article ; Online: Erratum: Multiple actions of doxorubicin on the sphingolipid network revealed by flux analysis.

Snider, Justin M / Trayssac, Magali / Clarke, Christopher J / Schwartz, Nicholas / Snider, Ashley J / Obeid, Lina M / Luberto, Chiara / Hannun, Yusuf A

Journal of lipid research

2021 Volume 62, Page(s) 100009

Language	English
Publishing date	2021-03-25
Publishing country	United States
Document type	Published Erratum
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1016/j.jlr.2020.100009
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Article ; Online: Targeting sphingosine kinase 1 in p53KO thymic lymphoma.

Velazquez, Fabiola N / Stith, Jeffrey L / Zhang, Leiqing / Allam, Amira M / Haley, John / Obeid, Lina M / Snider, Ashley J / Hannun, Yusuf A

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2023 Volume 37, Issue 11, Page(s) e23247

Abstract: Sphingosine kinase 1 (SK1) is a key sphingolipid enzyme that is upregulated in several types of cancer, including lymphoma which is a heterogenous group of malignancies. Treatment for lymphoma has improved significantly by the introduction of new ... ...

Abstract	Sphingosine kinase 1 (SK1) is a key sphingolipid enzyme that is upregulated in several types of cancer, including lymphoma which is a heterogenous group of malignancies. Treatment for lymphoma has improved significantly by the introduction of new therapies; however, subtypes with tumor protein P53 (p53) mutations or deletion have poor prognosis, making it critical to explore new therapeutic strategies in this context. SK1 has been proposed as a therapeutic target in different types of cancer; however, the effect of targeting SK1 in cancers with p53 deletion has not been evaluated yet. Previous work from our group suggests that loss of SK1 is a key event in mediating the tumor suppressive effect of p53. Employing both genetic and pharmacological approaches to inhibit SK1 function in Trp53KO mice, we show that targeting SK1 decreases tumor growth of established p53KO thymic lymphoma. Inducible deletion of Sphk1 or its pharmacological inhibition drive increased cell death in tumors which is accompanied by selective accumulation of sphingosine levels. These results demonstrate the relevance of SK1 in the growth and maintenance of lymphoma in the absence of p53 function, positioning this enzyme as a potential therapeutic target for the treatment of tumors that lack functional p53.
MeSH term(s)	Animals ; Mice ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Sphingosine/metabolism ; Neoplasms/metabolism ; Phosphotransferases (Alcohol Group Acceptor)/metabolism
Chemical Substances	sphingosine kinase (EC 2.7.1.-) ; Tumor Suppressor Protein p53 ; Sphingosine (NGZ37HRE42) ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-)
Language	English
Publishing date	2023-10-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202301417R
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Zs.MO 296: Show issues

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Article: A novel HSPB1

Espinoza, Keila S / Hermanson, Kyra N / Beard, Cameron A / Schwartz, Nicholas U / Snider, Justin M / Low, Benjamin E / Wiles, Michael V / Hannun, Yusuf A / Obeid, Lina M / Snider, Ashley J

Prostaglandins & other lipid mediators

2023 Volume 169, Page(s) 106769

Abstract: Charcot-Marie-Tooth Disease (CMT) is a commonly inherited peripheral polyneuropathy. Clinical manifestations for this disease include symmetrical distal polyneuropathy, altered deep tendon reflexes, distal sensory loss, foot deformities, and gait ... ...

Abstract	Charcot-Marie-Tooth Disease (CMT) is a commonly inherited peripheral polyneuropathy. Clinical manifestations for this disease include symmetrical distal polyneuropathy, altered deep tendon reflexes, distal sensory loss, foot deformities, and gait abnormalities. Genetic mutations in heat shock proteins have been linked to CMT2. Specifically, mutations in the heat shock protein B1 (HSPB1) gene encoding for heat shock protein 27 (Hsp27) have been linked to CMT2F and distal hereditary motor and sensory neuropathy type 2B (dHMSN2B) subtype. The goal of the study was to examine the role of an endogenous mutation in HSPB1 in vivo and to define the effects of this mutation on motor function and pathology in a novel animal model. As sphingolipids have been implicated in hereditary and sensory neuropathies, we examined sphingolipid metabolism in central and peripheral nervous tissues in 3-month-old Hsp
MeSH term(s)	Mice ; Animals ; Charcot-Marie-Tooth Disease/genetics ; Charcot-Marie-Tooth Disease/pathology ; Heat-Shock Proteins/genetics ; Mutation/genetics ; Disease Models, Animal ; Sphingolipids
Chemical Substances	Heat-Shock Proteins ; Sphingolipids
Language	English
Publishing date	2023-08-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1426962-4
ISSN	2212-196X ; 1098-8823 ; 0090-6980
ISSN (online)	2212-196X
ISSN	1098-8823 ; 0090-6980
DOI	10.1016/j.prostaglandins.2023.106769
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Article: Sphingosine kinase and sphingosine-1-phosphate: regulators in autoimmune and inflammatory disease.

Snider, Ashley J

International journal of clinical rheumatology

2013 Volume 8, Issue 4

Abstract: Sphingolipids and their metabolizing enzymes are beginning to be recognized as critical mediators in biological processes, specifically in inflammation and autoimmunity. Sphingosine kinases (SKs) and their lipid product sphingosine-1-phosphate (S1P) play ...

Abstract	Sphingolipids and their metabolizing enzymes are beginning to be recognized as critical mediators in biological processes, specifically in inflammation and autoimmunity. Sphingosine kinases (SKs) and their lipid product sphingosine-1-phosphate (S1P) play essential roles in inflammatory signaling processes, as well as disease development and progression. SKs can be activated by numerous growth factors and cytokines, including TNF-α and IL-1β, leading to the generation of S1P. S1P exerts its biological effects on intracellular and extracellular targets, such as S1P receptors. In addition to roles in inflammatory signaling pathways SKs, S1P and S1P receptors have been implicated in immune cell function and trafficking, specifically in lymphocytes. This review will discuss the contribution of the bioactive sphingolipid S1P, its generating enzyme SK, and its cell surface receptors in the inflammatory and autoimmune diseases systemic lupus erythematosus, arthritis and inflammatory bowel disease.
Language	English
Publishing date	2013-12-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2596494-X
ISSN	1758-4280 ; 1758-4272
ISSN (online)	1758-4280
ISSN	1758-4272
DOI	10.2217/ijr.13.40
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Article ; Online: PIM1 drives lipid droplet accumulation to promote proliferation and survival in prostate cancer.

Chauhan, Shailender S / Casillas, Andrea L / Vizzerra, Andres D / Liou, Hope / Clements, Amber N / Flores, Caitlyn E / Prevost, Christopher T / Kashatus, David F / Snider, Ashley J / Snider, Justin M / Warfel, Noel A

Oncogene

2023 Volume 43, Issue 6, Page(s) 406–419

Abstract: Lipid droplets (LDs) are dynamic organelles with a neutral lipid core surrounded by a phospholipid monolayer. Solid tumors exhibit LD accumulation, and it is believed that LDs promote cell survival by providing an energy source during energy deprivation. ...

Abstract	Lipid droplets (LDs) are dynamic organelles with a neutral lipid core surrounded by a phospholipid monolayer. Solid tumors exhibit LD accumulation, and it is believed that LDs promote cell survival by providing an energy source during energy deprivation. However, the precise mechanisms controlling LD accumulation and utilization in prostate cancer are not well known. Here, we show peroxisome proliferator-activated receptor α (PPARα) acts downstream of PIM1 kinase to accelerate LD accumulation and promote cell proliferation in prostate cancer. Mechanistically, PIM1 inactivates glycogen synthase kinase 3 beta (GSK3β) via serine 9 phosphorylation. GSK3β inhibition stabilizes PPARα and enhances the transcription of genes linked to peroxisomal biogenesis (PEX3 and PEX5) and LD growth (Tip47). The effects of PIM1 on LD accumulation are abrogated with GW6471, a specific inhibitor for PPARα. Notably, LD accumulation downstream of PIM1 provides a significant survival advantage for prostate cancer cells during nutrient stress, such as glucose depletion. Inhibiting PIM reduces LD accumulation in vivo alongside slow tumor growth and proliferation. Furthermore, TKO mice, lacking PIM isoforms, exhibit suppression in circulating triglycerides. Overall, our findings establish PIM1 as an important regulator of LD accumulation through GSK3β-PPARα signaling axis to promote cell proliferation and survival during nutrient stress.
MeSH term(s)	Male ; Humans ; Animals ; Mice ; Glycogen Synthase Kinase 3 beta ; Lipid Droplets/pathology ; PPAR alpha/genetics ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; Cell Proliferation ; Proto-Oncogene Proteins c-pim-1/genetics
Chemical Substances	Glycogen Synthase Kinase 3 beta (EC 2.7.11.1) ; PPAR alpha ; PIM1 protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins c-pim-1 (EC 2.7.11.1)
Language	English
Publishing date	2023-12-14
Publishing country	England
Document type	Journal Article
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/s41388-023-02914-0
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