ArticleThe Journal of biological chemistry2015
Sphingosine Kinase 1 Protects Hepatocytes from Lipotoxicity via Down-regulation of IRE1α Protein Expression.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 33 citations in OpenAlex.
- The relationship between plasma sphingosine-1-phosphate, plasma apolipoprotein M, obesity, and the risk of incident type 2 diabetes: a prospective cohort study.International journal of obesity (2005) · 2025Article
- Lipotoxicity: A New Perspective in Type 2 Diabetes Mellitus.Diabetes, metabolic syndrome and obesity : targets and therapy · 2025Review
- Review
- Review
- Targeting the SphK1/S1P/PFKFB3 axis suppresses hepatocellular carcinoma progression by disrupting glycolytic energy supply that drives tumor angiogenesis.Journal of translational medicine · 2024Article
- Integrative roles of sphingosine kinase in liver pathophysiology.Toxicological research · 2023Review
- The stress-responsive protein REDD1 and its pathophysiological functions.Experimental & molecular medicine · 2023Review
- The SphK1/S1P Axis Regulates Synaptic Vesicle Endocytosis via TRPC5 Channels.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- Hydrogen sulfide alleviates ischemia induced liver injury by repressing the SPHK1/S1P pathway.Annals of translational medicine · 2023Article
- One night of sleep deprivation induces release of small extracellular vesicles into circulation and promotes platelet activation by small EVs.Journal of cellular and molecular medicine · 2022Article
- Manifold Roles of Ceramide Metabolism in Non-Alcoholic Fatty Liver Disease and Liver Cancer.Advances in experimental medicine and biology · 2022Article
- Ceramide Transfer Protein (CERT): An Overlooked Molecular Player in Cancer.International journal of molecular sciences · 2021Review
- Cellular stress promotes NOD1/2-dependent inflammation via the endogenous metabolite sphingosine-1-phosphate.The EMBO journal · 2021Article
- Cell fate determined by the activation balance between PKR and SPHK1.Cell death and differentiation · 2021Article
- S1P Signaling Pathways in Pathogenesis of Type 2 Diabetes.Journal of diabetes research · 2021Article
- 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
- Generation of mice with hepatocyte-specific conditional deletion of sphingosine kinase 1.Transgenic research · 2020Article
- Role of Sphingosine Kinase in Type 2 Diabetes Mellitus.Frontiers in endocrinology · 2020Review
- Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication.Journal of lipid research · 2019Review
- Glutamate-oxaloacetate transaminase activity promotes palmitate lipotoxicity in rat hepatocytes by enhancing anaplerosis and citric acid cycle flux.The Journal of biological chemistry · 2019Article
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aberrant deposition of fat including free fatty acids in the liver often causes damage to hepatocytes, namely lipotoxicity, which is a key pathogenic event in the development and progression of fatty liver diseases. This study demonstrates a pivotal role of sphingosine kinase 1 (SphK1) in protecting hepatocytes from lipotoxicity. Exposure of primary murine hepatocytes to palmitate resulted in dose-dependent cell death, which was enhanced significantly in Sphk1-deficient cells. In keeping with this, expression of dominant-negative mutant SphK1 also markedly promoted palmitate-induced cell death. In contrast, overexpression of wild-type SphK1 profoundly protected hepatocytes from lipotoxicity. Mechanistically, the protective effect of SphK1 is attributable to suppression of ER stress-mediated pro-apoptotic pathways, as reflected in the inhibition of IRE1α activation, XBP1 splicing, JNK phosphorylation, and CHOP induction. Of note, SphK1 inhibited the IRE1α pathway by reducing IRE1α expression at the transcriptional level. Moreover, S1P mimicked the effect of SphK1, suppressing IRE1α expression in a receptor-dependent manner. Furthermore, enforced overexpression of IRE1α significantly blocked the protective effect of SphK1 against lipotoxicity. Therefore, this study provides new insights into the role of SphK1 in hepatocyte survival and uncovers a novel mechanism for protection against ER stress-mediated cell death.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.