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Acta Pharmacol Sin ; 45(5): 988-1001, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38279043

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disease that is substantially associated with obesity-induced chronic inflammation. Macrophage activation and macrophage-medicated inflammation play crucial roles in the development and progression of NAFLD. Furthermore, fibroblast growth factor receptor 1 (FGFR1) has been shown to be essentially involved in macrophage activation. This study investigated the role of FGFR1 in the NAFLD pathogenesis and indicated that a high-fat diet (HFD) increased p-FGFR1 levels in the mouse liver, which is associated with increased macrophage infiltration. In addition, macrophage-specific FGFR1 knockout or administration of FGFR1 inhibitor markedly protected the liver from HFD-induced lipid accumulation, fibrosis, and inflammatory responses. The mechanistic study showed that macrophage-specific FGFR1 knockout alleviated HFD-induced liver inflammation by suppressing the activation of MAPKs and TNF signaling pathways and reduced fat deposition in hepatocytes, thereby inhibiting the activation of hepatic stellate cells. In conclusion, the results of this research revealed that FGFR1 could protect the liver of HFD-fed mice by inhibiting MAPKs/TNF-mediated inflammatory responses in macrophages. Therefore, FGFR1 can be employed as a target to prevent the development and progression of NAFLD.


Asunto(s)
Dieta Alta en Grasa , Macrófagos , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos , Factor de Necrosis Tumoral alfa , Animales , Dieta Alta en Grasa/efectos adversos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Ratones , Masculino , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/etiología , Factor de Necrosis Tumoral alfa/metabolismo , Ratones Noqueados , Hígado/patología , Hígado/metabolismo , Transducción de Señal , Inflamación/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos
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