Blockade of YAP alleviates hepatic fibrosis through accelerating apoptosis and reversion of activated hepatic stellate cells

Abstract

Yes-associated protein (YAP) is a significant downstream protein in the Hippo signaling pathway with important functions in cell proliferation, apoptosis, invasion and migration. YAP also plays a role in the progression and development of various liver diseases. In hepatic fibrosis development and reversion, the proliferation and apoptosis of activated hepatic stellate cells (HSCs) play a critical role. However, the contribution of YAP to hepatic fibrosis progression and reversion and the underlying mechanism have not been investigated. Here we investigated the expression and function of YAP in the proliferation and apoptosis of activated HSCs. We found that YAP expression was increased in liver fibrosis tissues from CCl4-induced model mice and restored to normal level after stopping CCl4 injection and 6 weeks of spontaneously recovery. YAP expression was elevated in HSC-T6 cells treated with TGF-β1 and recovered after MDI treatment. Silencing of YAP inhibited the activation and proliferation of HSC-T6 cells stimulated by TGF-β1. In addition, the apoptosis of activated HSC-T6 cells silenced for YAP was slightly enhanced. Furthermore, over-expression of YAP repressed the reversion of activated HSC-T6 cells mediated by MDI reversal. We found that HSC-T6 cells activated by TGF-β1 showed higher levels of nuclear YAP compared with MDI-treated cells, indicating that YAP was activated in HSC-T6 cells treated by TGF-β1. We also found that loss of YAP attenuated Wnt/β-catenin pathway activity in activated HSC-T6 cells. Treatment of VP, an inhibitor of the YAP-TEAD complex, reduced both activation and proliferation of HSC-T6 cells and increased apoptosis. Together these results indicated that reduced expression of YAP contributes to acquisition of the quiescent phenotype in HSCs. Our results suggest that YAP may be a useful target in HSCs activation and reversion.