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The Interplay between Liver Sinusoidal Endothelial Cells, Platelets, and Neutrophil Extracellular Traps in the Development and Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease.

Iulia MinciunaMadalina Gabriela TaruBogdan ProcopetHoria Stefanescu
Published in: Journal of clinical medicine (2024)
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a societal burden due to the lack of effective treatment and incomplete pathophysiology understanding. This review explores the intricate connections among liver sinusoidal endothelial cells (LSECs), platelets, neutrophil extracellular traps (NETs), and coagulation disruptions in MASLD pathogenesis. In MASLD's early stages, LSECs undergo capillarization and dysfunction due to excessive dietary macronutrients and gut-derived products. Capillarization leads to ischemic changes in hepatocytes, triggering pro-inflammatory responses in Kupffer cells (KCs) and activating hepatic stellate cells (HSCs). Capillarized LSECs show a pro-inflammatory phenotype through adhesion molecule overexpression, autophagy loss, and increased cytokines production. Platelet interaction favors leucocyte recruitment, NETs formation, and liver inflammatory foci. Liver fibrosis is facilitated by reduced nitric oxide, HSC activation, profibrogenic mediators, and increased angiogenesis. Moreover, platelet attachment, activation, α-granule cargo release, and NETs formation contribute to MASLD progression. Platelets foster fibrosis and microthrombosis, leading to parenchymal extinction and fibrotic healing. Additionally, platelets promote tumor growth, epithelial-mesenchymal transition, and tumor cell metastasis. MASLD's prothrombotic features are exacerbated by insulin resistance, diabetes, and obesity, manifesting as increased von Willebrand factor, platelet hyperaggregability, hypo-fibrinolysis, and a prothrombotic fibrin clot structure. Improving LSEC health and using antiplatelet treatment appear promising for preventing MASLD development and progression.
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