p-CREB-1 promotes hepatic fibrosis through the transactivation of transforming growth factor-β1 expression in rats.
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 (CCl4)‑induced 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.
Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
Pei
P
Wang
Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China.
Liang
L
Deng
Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
Chunbo
C
Zhuang
Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
Chunwei
C
Cheng
Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
Keshu
K
Xu
D000818:Animals; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D017362:Cyclic AMP Response Element-Binding Protein; D053773:Transforming Growth Factor beta1