ArticleLiver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society2019
Hyperglycemia-Triggered Sphingosine-1-Phosphate and Sphingosine-1-Phosphate Receptor 3 Signaling Worsens Liver Ischemia/Reperfusion Injury by Regulating M1/M2 Polarization.
Article in Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
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22 citing papers in PubMed, 1 synthesis or guideline pooled it, 35 citations in OpenAlex.
- Peri-Liver Transplant Hyperglycemia: Mechanisms, Associated Factors, Consequences, and Management - A Systematic Review.Endocrinology, diabetes & metabolism · 2025Pooled it
- Mitophagy in Hepatic Ischemia-Reperfusion Injury: From Mitochondrial Dysfunction to Therapeutic Targeting.Biomolecules · 2026Review
- Oxidized Phospholipids Aggravate Hepatic Ischemia/Reperfusion Injury by Promoting Macrophage M1 Polarization Via Regulating the Wnt/β-catenin/Autophagy Axis.Inflammation · 2026Article
- Metabolic changes after hepatectomy: Implications for perioperative management and long-term outcomes.World journal of gastrointestinal pathophysiology · 2025Article
- SUCNR1 Deficiency Alleviates Liver Ischemia-Reperfusion Injury by Regulating Kupffer Cell Activation and Polarization Through the ERK/NF-κB Pathway in Mice.Inflammation · 2025Article
- Nuclear receptor-driven immunometabolic crosstalk: immune-centric pharmacology targeting the inflamed nexus.Frontiers in cell and developmental biology · 2025Review
- Broad and diverse roles of sphingosine-1-phosphate/sphingosine-1-phosphate receptors in the prostate.iScience · 2024Article
- Extracellular vesicles containing GAS6 protect the liver from ischemia-reperfusion injury by enhancing macrophage efferocytosis via MerTK-ERK-COX2 signaling.Cell death discovery · 2024Article
- S1PR3 suppresses the inflammatory response and extracellular matrix degradation in human nucleus pulposus cells.Experimental and therapeutic medicine · 2024Article
- PPM1G regulates hepatic ischemia/reperfusion injury through STING-mediated inflammatory pathways in macrophages.Immunity, inflammation and disease · 2024Article
- Density of Sphingosine-1-Phosphate Receptors Is Altered in Cortical Nerve-Terminals of Insulin-Resistant Goto-Kakizaki Rats and Diet-Induced Obese Mice.Neurochemical research · 2024Article
- Bioinformatics to Identify Biomarkers of Diabetic Nephropathy based on Sphingolipid Metabolism and their Molecular Mechanisms.Current diabetes reviews · 2024Article
- The Role of Gut Microbiota and Circadian Rhythm Oscillation of Hepatic Ischemia-Reperfusion Injury in Diabetic Mice.Biomedicines · 2023Article
- Dissecting the Therapeutic Mechanisms of Sphingosine-1-Phosphate Receptor Agonism during Ischaemia and Reperfusion.International journal of molecular sciences · 2023Article
- Article
- Inhibition of Notch activity suppresses hyperglycemia-augmented polarization of macrophages to the M1 phenotype and alleviates acute pancreatitis.Clinical science (London, England : 1979) · 2022Article
- Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization.Open medicine (Warsaw, Poland) · 2022Article
- Doxepin Exacerbates Renal Damage, Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Urinary Chromium Loss in Obese Mice.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Suberoylanilide hydroxamic acid alleviates orthotopic liver transplantation‑induced hepatic ischemia‑reperfusion injury by regulating the AKT/GSK3β/NF‑κB and AKT/mTOR pathways in rat Kupffer cells.International journal of molecular medicine · 2020Article
- Macrophage Regnase-1 Deletion Deteriorates Liver Ischemia/Reperfusion Injury Through Regulation of Macrophage Polarization.Frontiers in physiology · 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
Hyperglycemia aggravates hepatic ischemia/reperfusion injury (IRI), but the underlying mechanism for the aggravation remains elusive. Sphingosine-1-phosphate (S1P) and sphingosine-1-phosphate receptors (S1PRs) have been implicated in metabolic and inflammatory diseases. Here, we discuss whether and how S1P/S1PRs are involved in hyperglycemia-related liver IRI. For our in vivo experiment, we enrolled diabetic patients with benign hepatic disease who had liver resection, and we used streptozotocin (STZ)-induced hyperglycemic mice or normal mice to establish a liver IRI model. In vitro bone marrow-derived macrophages (BMDMs) were differentiated in high-glucose (HG; 30 mM) or low-glucose (LG; 5 mM) conditions for 7 days. The expression of S1P/S1PRs was analyzed in the liver and BMDMs. We investigated the functional and molecular mechanisms by which S1P/S1PRs may influence hyperglycemia-related liver IRI. S1P levels were higher in liver tissues from patients with diabetes mellitus and mice with STZ-induced diabetes. S1PR3, but not S1PR1 or S1PR2, was activated in liver tissues and Kupffer cells under hyperglycemic conditions. The S1PR3 antagonist CAY10444 attenuated hyperglycemia-related liver IRI based on hepatic biochemistry, histology, and inflammatory responses. Diabetic livers expressed higher levels of M1 markers but lower levels of M2 markers at baseline and after ischemia/reperfusion. Dual-immunofluorescence staining showed that hyperglycemia promoted M1 (CD68/CD86) differentiation and inhibited M2 (CD68/CD206) differentiation. Importantly, CAY10444 reversed hyperglycemia-modulated M1/M2 polarization. HG concentrations in vitro also triggered S1P/S1PR3 signaling, promoted M1 polarization, inhibited M2 polarization, and enhanced inflammatory responses compared with LG concentrations in BMDMs. In contrast, S1PR3 knockdown significantly retrieved hyperglycemia-modulated M1/M2 polarization and attenuated inflammation. In conclusion, our study reveals that hyperglycemia specifically triggers S1P/S1PR3 signaling and exacerbates liver IRI by facilitating M1 polarization and inhibiting M2 polarization, which may represent an effective therapeutic strategy for liver IRI in diabetes.
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