p-CREB-1 promotes hepatic fibrosis through the transactivation of transforming growth factor-β1 expression in rats
International Journal of Molecular Medicine
Phosphorylated cAMP-responsive element binding protein-1 (p-CREB-1) is an important transcription factor which has been reported to be implicated in fibrogenesis. However, the association between p-CREB-1 and transforming growth factor-β1 (TGF-β1)-mediated liver fibrogenesis remains poorly understood. In the present study, exogenous TGF-β1 recombinant protein was used to activate hepatic stellate cells (HSCs), and we established a rat model of tetrachloromethane (CCl 4 )-induced liver fibrosis.
... ced liver fibrosis. Loss-and gain-of-function studies were performed to examine the role of p-CREB-1 in liver fibrogenesis, and the detailed mechanism responsible for these effects was further explored using chromatin immunoprecipitation and luciferase reporter gene assays. We found that p-CREB-1 expression was significantly upregulated in a rat model of hepatic fibrosis. We also demonstrated that p-CREB-1 increased TGF-β1 expression and auto-induction in HSCs, through directly binding to the CRE site within the TGF-β1 promoter in order to enhance its transcriptional activity. Moreover, lentivirus-mediated CREB-1 overexpression promoted hepatic fibrogenesis in rats. These findings suggest that p-CREB-1 may function as a potent profibrogenic factor through the transactivation of TGF-β1 expression in liver fibrosis. Abbreviations: p-CREB-1, phosphorylated cyclic adenosine 3',5'-monophosphate-responsive element binding protein-1; TGF-β1, transforming growth factor-β1; HSCs, hepatic stellate cells; CCl 4 , tetrachloromethane; RT-qPCR, reverse transcription quantitativepolymerase chain reaction; ChIP, chromatin immunoprecipitation