-regulated activation of hepatic stellate cells and liver fibrosis by TGF-β signaling.

The Hedgehog (Hh) signaling pathway is correlated with hepatic stellate cells (HSCs) activation and liver fibrosis. is a key transcription effector of Hh signaling. However, the role of in HSC-mediated liver fibrosis progression is largely unknown. In the present study, we investigated the effect of on liver fibrogenesis and its possible mechanism using conditional knockout (cKO) mice and HSC models. Wild-type (WT) and ; male mice were exposed to CCl for 1 mo to induce liver fibrosis. Primary HSCs were isolated from mice and the transition of HSCs into a myofibroblastic phenotype was evaluated. Livers from mice underwent histological, immunohistochemical, and immunofluorescence analyses. The expression levels of proteins and genes were evaluated by Western blot (WB) analysis and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. RNA-seq was used to screen differentially expressed genes. Results showed that CCl treatment induced liver fibrosis, promoted HSCs activation and proliferation, and upregulated Hh signaling activity. The cKO of in ; mice decreased liver fibrosis as well as HSC activation and proliferation. In vitro studies showed that KO of in HSCs blocked cell proliferation and activation by decrease of cyclin D1/D2 expression. The RNA-seq results revealed that the expression levels ligands were downregulated in KO HSCs. Furthermore, overexpression of rescued proliferation and activation of HSCs by upregulation of TGF-β signaling activity. Our data demonstrated that regulated HSC activation and liver fibrosis by TGF-β signaling, thus providing support for future Gli2-based investigations of liver fibrosis therapy. is a key transcription effector of Hh signaling. We found that Hh/Gli2 signaling activity was upregulated in CCl-induced liver fibrosis. Conditional deletion of the gene in HSCs ameliorated CCl-induced liver fibrosis and HSCs activation. Moreover, promoted activation of HSCs through upregulation of cyclin expression and TGF-β signaling activity. Thus, our data provide strong support for future investigations on inhibition to slow liver fibrosis progression in humans.