title: Activation of the miR-34a/SIRT1/p53 Signaling Pathway Contributes to the Progress of Liver Fibrosis via Inducing Apoptosis in Hepatocytes but Not in HSCs.
abstract: Liver fibrosis results from a sustained wound healing response to chronic liver injury, and the activation of nonparenchymal hepatic stellate cells (HSCs) is the pivotal process. MicroRNA-34a (miR-34a) is the direct target gene of p53 and activates p53 through sirtuin 1 (SIRT1) simultaneously. The miR-34a/SIRT1/p53 signaling pathway thus forms a positive feedback loop wherein p53 induces miR-34a and miR-34a activates p53 by inhibiting SIRT1, playing an important role in cell proliferation and apoptosis. miR-34a expression has been found to be increased in animal models or in human patients with different liver diseases, including liver fibrosis. However, the exact role of this classical miR-34a/SIRT1/p53 signaling pathway in liver fibrosis remains unclear. In the present study, using a CCl4-induced rat liver fibrosis model, we found that the miR-34a/SIRT1/p53 signaling pathway was activated and could be inhibited by SIRT1 activator SRT1720. Further studies showed that the miR-34a/SIRT1/p53 signaling pathway was activated in hepatocytes but not in HSCs. The activation of this pathway in hepatocytes resulted in the apoptosis of hepatocytes and thus activated HSCs. Our data indicate that the miR-34a/SIRT1/p53 signaling pathway might be a promising therapeutic target for liver fibrosis.
authors.affiliation: Department of General Surgery, the China-Japan Union Hospital, Jilin University, Changchun 130021, China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Tian
authors.affiliation: Department of General Surgery, the China-Japan Union Hospital, Jilin University, Changchun 130021, China.
authors.forename: Fu-Jian
authors.initials: FJ
authors.lastname: Ji
authors.affiliation: Department of General Surgery, the China-Japan Union Hospital, Jilin University, Changchun 130021, China.
authors.forename: Hong-Liang
authors.initials: HL
authors.lastname: Zang
authors.affiliation: Department of General Surgery, the China-Japan Union Hospital, Jilin University, Changchun 130021, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Cao
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D018920:Coculture Techniques; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C522425:MIRN34 microRNA, human; C560944:MIRN34 microRNA, rat; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C447939:SIRT1 protein, human; C488368:Sirt1 protein, rat; D056564:Sirtuin 1