ArticleDiabetologia2025
Effect of lipotoxic hepatocyte-derived extracellular vesicles in pancreas inflammation: essential role of macrophage TLR4 in beta cell functionality.
Article in Diabetologia, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Pancreatic-liver crosstalk, novel molecular mediators, and 2025 therapeutic breakthroughs.World journal of methodology · 2026Review
- Extracellular Vesicle-Mediated Local and Systemic Communication in Metabolic Diseases.International journal of molecular sciences · 2026Review
- Review
- Emerging Insights into the Liver-Pancreas Axis: A Central Hub in the Pathogenesis of Diabetes and Metabolic Diseases.Biomolecules · 2026Review
- Review
- Liver-pancreas communication in disease and drug development.Acta pharmaceutica Sinica. B · 2026Review
- Extracellular Vesicles: Orchestrators of Intrahepatic and Systemic Crosstalk in Metabolic Dysfunction-Associated Steatotic Liver Disease.Pharmaceutics · 2026Review
- Targeted regulation of adipose tissue macrophages from an immunometabolic perspective: a novel therapeutic approach for obesity-related metabolic disorders.Frontiers in immunology · 2026Review
- Toll-Like Receptors in Diabetes: Immunometabolic Mechanisms and Emerging Precision Therapeutic Strategies.Journal of inflammation research · 2026Review
- Extracellular vesicle-mediated intercellular and interorgan crosstalk of pancreatic islet in health and diabetes.Frontiers in endocrinology · 2023Review
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Authors and funding
12 authors.
Funding
Abstract
aims/hypothesisMetabolic dysfunction-associated steatotic liver disease (MASLD) is a common feature of obesity and type 2 diabetes. Under lipotoxic stress, hepatocytes release small extracellular vesicles (sEVs) which act locally and contribute to MASLD progression, but their role in beta cell function and development of type 2 diabetes remains largely unexplored. We aimed to examine whether hepatocyte-derived sEVs (Hep-sEVs) under lipotoxic conditions impact on liver and pancreas inflammation and subsequent effects on beta cell function.
methodsPrimary mouse hepatocytes and Huh7 human hepatocytes were treated with palmitic acid and Hep-sEVs were purified from the culture medium by differential ultracentrifugation. In vitro and in vivo approaches were used to decipher the role of Hep-sEVs in liver and pancreas inflammation and beta cell dysfunction in mouse and human pancreatic islets. The contribution of the Toll-like receptor 4 (TLR4) to Hep-sEV-mediated effects was investigated in pancreatic islets from myeloid-specific TLR4-deficient mice.
resultsLipotoxic Hep-sEVs targeted pancreatic islet macrophages and induced TLR4-mediated inflammation. The subsequent inflammatory response downregulated beta cell identity genes and impaired glucose-stimulated insulin secretion in both INS-1 beta cells (p<0.05) and isolated pancreatic islets from mice (p<0.01) and humans (p<0.05). Specific deletion of TLR4 in macrophages protected pancreatic islets against inflammation and the impairment of glucose-stimulated insulin secretion induced by lipotoxic Hep-sEVs. Chronic administration of lipotoxic Hep-sEVs in lean mice induced liver and pancreas inflammation through the recruitment of immune cells. This intervention induced hepatocyte injury and fibrotic damage together with detrimental immunometabolic systemic effects. Insulin resistance in hepatocytes (p<0.01) and a compensatory insulin secretion (p<0.001) that prevented glucose intolerance were also observed in mice treated with lipotoxic Hep-sEVs. CONCLUSIONS/
interpretationThis study has provided evidence of liver and pancreas inflammation and beta cell dysfunction induced by lipotoxic Hep-sEVs. Our data also envision TLR4-mediated signalling in islet macrophages as a key mediator of the effects of lipotoxic Hep-sEVs on beta cell function.
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