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Aims/hypothesis <p>Metabolic 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.</p> Methods <p>Primary 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.</p> Results <p>Lipotoxic 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 (<i>p</i>&lt;0.05) and isolated pancreatic islets from mice (<i>p</i>&lt;0.01) and humans (<i>p</i>&lt;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 (<i>p</i>&lt;0.01) and a compensatory insulin secretion (<i>p</i>&lt;0.001) that prevented glucose intolerance were also observed in mice treated with lipotoxic Hep-sEVs.</p> Conclusions/interpretation <p>This 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.</p> Graphical Abstract <p></p>

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Effect of lipotoxic hepatocyte-derived extracellular vesicles in pancreas inflammation: essential role of macrophage TLR4 in beta cell functionality

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月19日

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  • Rosa Alén,
  • Irma Garcia-Martinez,
  • Nadia Cobo-Vuilleumier,
  • Elisa Fernández-Millán,
  • Paula Gallardo-Villanueva,
  • Vitor Ferreira,
  • Manuel Izquierdo,
  • María Ángeles Moro,
  • Ignacio Lizasoain,
  • Natalia Nieto,
  • Benoit R. Gauthier,
  • Ángela M. Valverde

摘要

Aims/hypothesis

Metabolic 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.

Methods

Primary 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.

Results

Lipotoxic 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/interpretation

This 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.

Graphical Abstract