ArticleDiabetologia2014
Involvement of sphingosine 1-phosphate in palmitate-induced insulin resistance of hepatocytes via the S1P2 receptor subtype.
Article in Diabetologia, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 1 of them a synthesis that pooled it.
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Who cites it
46 citing papers in PubMed, 1 synthesis or guideline pooled it, 87 citations in OpenAlex.
- The Role of Fatty Acids in Ceramide Pathways and Their Influence on Hypothalamic Regulation of Energy Balance: A Systematic Review.International journal of molecular sciences · 2021Pooled it
- Sphingolipids and Atherosclerosis.Current atherosclerosis reports · 2026Review
- 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
- Crosstalk Between Skeletal Muscle and Proximal Connective Tissues in Lipid Dysregulation in Obesity and Type 2 Diabetes.Metabolites · 2025Review
- Sphingosine 1-Phosphate Regulates Obesity and Glucose Homeostasis.International journal of molecular sciences · 2024Review
- Effect of FTY720P on lipid accumulation in HEPG2 cells.Scientific reports · 2023Article
- Pharmacometabolomic Approach to Investigate the Response to Metformin in Patients with Type 2 Diabetes: A Cross-Sectional Study.Biomedicines · 2023Article
- Chicoric acid ameliorates palmitate-induced sphingosine 1-phosphate signaling pathway in the PBMCs of patients with newly diagnosed type 2 diabetes.Journal of diabetes and metabolic disorders · 2023Article
- ORMDL in metabolic health and disease.Pharmacology & therapeutics · 2023Review
- Opposing Roles of Sphingosine 1-Phosphate Receptors 1 and 2 in Fat Deposition and Glucose Tolerance in Obese Male Mice.Endocrinology · 2023Article
- Sphingolipid metabolism in brain insulin resistance and neurological diseases.Frontiers in endocrinology · 2023Review
- Differences in lipid metabolism in acquired versus preexisting glucose intolerance during gestation: role of free fatty acids and sphingosine-1-phosphate.Lipids in health and disease · 2022Article
- Associations between red blood cell count and metabolic dysfunction-associated fatty liver disease(MAFLD).PloS one · 2022Article
- Anti-inflammatory role of Gpnmb in adipose tissue of mice.Scientific reports · 2021Article
- Barrier maintenance by S1P during inflammation and sepsis.Tissue barriers · 2021Review
- Central Acting Hsp10 Regulates Mitochondrial Function, Fatty Acid Metabolism, and Insulin Sensitivity in the Hypothalamus.Antioxidants (Basel, Switzerland) · 2021Article
- Red Blood Cell Count: An Unrecognized Risk Factor for Nonalcoholic Fatty Liver Disease.Frontiers in endocrinology · 2021Article
- AqueousJournal of diabetes and metabolic disorders · 2020Article
- Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS.Journal of cellular signaling · 2020Article
- Sphingosine kinase 1 is required for myristate-induced TNFα expression in intestinal epithelial cells.Prostaglandins & other lipid mediators · 2020Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisEnhanced plasma levels of NEFA have been shown to induce hepatic insulin resistance, which contributes to the development of type 2 diabetes. Indeed, sphingolipids can be formed via a de novo pathway from the saturated fatty acid palmitate and the amino acid serine. Besides ceramides, sphingosine 1-phosphate (S1P) has been identified as a major bioactive lipid mediator. Therefore, our aim was to investigate the generation and function of S1P in hepatic insulin resistance.
methodsThe incorporation of palmitate into sphingolipids was performed by rapid-resolution liquid chromatography-MS/MS in primary human and rat hepatocytes. The influence of S1P and the involvement of S1P receptors in hepatic insulin resistance was examined in human and rat hepatocytes, as well as in New Zealand obese (NZO) mice.
resultsPalmitate induced an impressive formation of extra- and intracellular S1P in rat and human hepatocytes. An elevation of hepatic S1P levels was observed in NZO mice fed a high-fat diet. Once generated, S1P was able, similarly to palmitate, to counteract insulin signalling. The inhibitory effect of S1P was abolished in the presence of the S1P2 receptor antagonist JTE-013 both in vitro and in vivo. In agreement with this, the immunomodulator FTY720-phosphate, which binds to all S1P receptors except S1P2, was not able to inhibit insulin signalling. CONCLUSIONS/
interpretationThese data indicate that palmitate is metabolised by hepatocytes to S1P, which acts via stimulation of the S1P2 receptor to impair insulin signalling. In particular, S1P2 inhibition could be considered as a novel therapeutic target for the treatment of insulin resistance.
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