Effect of lipotoxic hepatocyte‑derived extracellular vesicles in pancreas inflammation: essential role of macrophage TLR4 in beta cell functionality – published online 19/05/2025

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

Metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes share interconnected pathophysiological mechanisms that mutually worsen disease progression and associated comorbidities. In this issue, Alén and Garcia-Martinez et al (https://doi.org/10.1007/s00125-025-06445-z) explore how small extracellular vesicles released by hepatocytes under MASLD-related lipotoxic stress (Hep-sEVs) affect pancreatic function. Their study demonstrates that Hep-sEVs target the pancreas, triggering inflammation and disrupting beta cell function. Using in vitro models, the authors show that interactions between pancreatic macrophages and beta cells mediated by lipotoxic Hep-sEVs result in impaired glucose-stimulated insulin secretion and the downregulation of genes essential for beta cell identity. These effects are mitigated when Toll-like receptor 4 (TLR4) is deleted in islet macrophages. Furthermore, administration of lipotoxic Hep-sEVs to lean mice causes hepatocyte damage and fibrosis, accompanied by systemic immunometabolic disturbances. These mice exhibit hepatic insulin resistance alongside a compensatory increase in insulin secretion that preserves glucose tolerance. The authors conclude that the TLR4-mediated effects of Hep-sEV are key contributors to MASLD-associated beta cell dysfunction, presenting a therapeutic target for early intervention in MASLD and potentially for the prevention of type 2 diabetes.

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