Depletion of Tgfbr2 in hepatocytes alleviates liver fibrosis and restores hepatic function in fibrotic mice.
J Dig Dis
; 24(1): 39-50, 2023 Jan.
Article
en En
| MEDLINE
| ID: mdl-36967587
ABSTRACT
OBJECTIVES:
Previous studies have demonstrated the pivotal role of transforming growth factor (TGF)-ß signaling in activating hepatic stellate cells during liver fibrosis. In this study we aimed to demonstrate the effects and underlying mechanism of TGF-ß signaling in hepatocytes on hepatic fibrogenesis.METHODS:
Hepatocyte-specific Tgfbr2-knockout (Tgfbr2HKO ) mice were generated by AAV8-TBG-Cre injection via the tail vein of Tgfbr2f/f mice. CCl4 was injected intraperitoneally twice a week for 4 weeks to establish the fibrotic mouse model. The expression of the fibrogenesis markers was evaluated by immunohistochemistry, western blot, and real-time polymerase chain reaction (PCR). RNA-seq analysis was used to detect the transcriptional profiles of primary hepatocytes isolated from Tgfbr2HKO mice and control mice.RESULTS:
The expression of TßR2 (Tgfbr2) was markedly upregulated in hepatocytes of the fibrotic liver. Tgfbr2 depletion in hepatocytes decreased the expressions of profibrogenic markers (Col1a1 and Acta2) in the CCl4 -treated fibrotic liver. RNA-seq analysis revealed that Tgfbr2 deletion in hepatocytes significantly reduced the inflammatory response and suppressed epithelial-mesenchymal transition of hepatocytes accompanied by upregulation of the metabolic pathways during liver fibrosis. Moreover, the expressions of hepatocyte nuclear factors (HNFs), including Hnf4α, Foxa1, Foxa2, and Foxa3, which are important for maintaining liver metabolism and homeostasis, were decreased in fibrotic livers and significantly increased after Tgfbr2 blockade.CONCLUSION:
Blocking the TGF-ß signaling pathway in hepatocytes reduces hepatic fibrosis and improves hepatic function in fibrotic livers.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Hepatocitos
/
Receptor Tipo II de Factor de Crecimiento Transformador beta
/
Cirrosis Hepática
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Dig Dis
Año:
2023
Tipo del documento:
Article
País de afiliación:
China