ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2019
Sphingosine kinase 2 promotes lipotoxicity in pancreatic β-cells and the progression of diabetes.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 27 citations in OpenAlex.
- Sphingosine kinase 2 regulates adipocyte browning and whole-body metabolism.Science advances · 2026Article
- Higher Plasma Sphingosine-1-Phosphate Levels in Type 2 Diabetic Patients Have a Non-Linear Relationship with the Disease Prognostic Indices and Microvascular Complications: A Cross-Sectional Saudi Study.Journal of clinical medicine · 2026Article
- Fingolimod Improves Anxiety-like Behavior and Modulates Sphingosine-1-Phosphate Receptors Gene Expression in a Diabetic Mouse Model.Biomolecules · 2025Article
- Metformin Induces Changes in Sphingosine-1-Phosphate-Related Signaling in Diabetic Mice Brain.International journal of molecular sciences · 2025Article
- Opaganib Promotes Weight Loss and Suppresses High-Fat Diet-Induced Obesity and Glucose Intolerance.Diabetes, metabolic syndrome and obesity : targets and therapy · 2025Article
- Sphingosine kinase 2 and p62 regulation are determinants of sexual dimorphism in hepatocellular carcinoma.Molecular metabolism · 2024Article
- Sphingosine Kinase 2 Knockout Mice Resist HFD-Induced Obesity Through Increasing Energy Expenditure.International journal of endocrinology and metabolism · 2023Article
- ORMDL in metabolic health and disease.Pharmacology & therapeutics · 2023Review
- The Dark Side of Sphingolipids: Searching for Potential Cardiovascular Biomarkers.Biomolecules · 2023Review
- A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury.International journal of molecular sciences · 2022Review
- To Be or Not to Be: The Divergent Action and Metabolism of Sphingosine-1 Phosphate in Pancreatic Beta-Cells in Response to Cytokines and Fatty Acids.International journal of molecular sciences · 2022Review
- Sphingosine-1 Phosphate Lyase Regulates Sensitivity of Pancreatic Beta-Cells to Lipotoxicity.International journal of molecular sciences · 2021Article
- Barrier maintenance by S1P during inflammation and sepsis.Tissue barriers · 2021Review
- Identification of circulating sphingosine kinase-related metabolites for prediction of type 2 diabetes.Journal of translational medicine · 2021Article
- Sphingolipids in metabolic disease: The good, the bad, and the unknown.Cell metabolism · 2021Review
- Lipotoxic Impairment of Mitochondrial Function in β-Cells: A Review.Antioxidants (Basel, Switzerland) · 2021Review
- Ceramides and Sphingosino-1-Phosphate in Obesity.Frontiers in endocrinology · 2021Review
- The Role of Pi, Glutamine and the Essential Amino Acids in Modulating the Metabolism in Diabetes and Cancer.Journal of diabetes and metabolic disorders · 2020Review
- Regulation of hepatic insulin signaling and glucose homeostasis by sphingosine kinase 2.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Review
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Loss of functional β-cell mass caused by lipotoxicity is a key pathogenic factor in the development of type 2 diabetes mellitus (T2DM). We have previously reported that sphingosine kinase (SK)1 is an endogenous protector of β-cells against lipotoxicity. The current study reports that SK2, another isoform of SK, is a crucial mediator of lipotoxicity in β-cells. Exposure of β-cells to palmitatic acid (PA), a saturated free fatty acid, resulted in a nearly 2-fold increase in SK2 expression, which paralleled the induction of cell death in a similar dose- and time-dependent fashion. Silencing SK2 expression by its specific small interfering RNAs significantly inhibited PA-induced cell death and caspase-3 activation, whereas overexpression of SK2 promoted lipotoxicity in β-cells. Mechanistically, upon exposure to PA, endogenous SK2 was shuttled from the nucleus to the cytoplasm, where it interacted with B-cell lymphoma-extra-large (Bcl-xL), leading to mitochondrial apoptotic pathway activation and cell death. By blocking SK2 translocation and its interaction with Bcl-xL, either the nuclear export signal mutant (L423A/L425A) or the BH3 domain mutant (L219A) of SK2 significantly attenuated β-cell lipotoxicity. Furthermore, SK2 deficiency in mice significantly prevented the loss of β-cell mass, preserved insulin production, and ameliorated the diabetic phenotype in an established T2DM model induced by feeding a high-fat diet accompanied by administration of streptozotocin. These findings provide the first evidence, in vitro and in vivo, of a critical role for SK2 in mediating β-cell lipotoxicity and the progression of diabetes.-Song, Z., Wang, W., Li, N., Yan, S., Rong, K., Lan, T., Xia, P. Sphingosine kinase 2 promotes lipotoxicity in pancreatic β-cells and the progression of diabetes.
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