Ablation of serum response factor in hepatic stellate cells attenuates liver fibrosis

Trans-differentiation, or activation, of hepatic stellate cells (HSCs) is a hallmark event in liver fibrosis although the underlying mechanism is not fully appreciated. Serum response factor (SRF) is a pleiotropic sequence-specific transcription factor with a ubiquitous expression pattern. In the present study, we investigated the effect of HSC-specific ablation of SRF on liver fibrosis in vivo and the underlying mechanism. We report that SRF bound to the promoter regions of pro-fibrogenic genes, including collagen type I (Col1a1/Col1a2) and alpha smooth muscle actin (Acta2), with greater affinity in activated HSCs compared to quiescent HSCs. Ablation of SRF in HSCs in vitro downregulated the expression of fibrogenic genes by dampening the accumulation of active histone marks. SRF also interacted with MRTF-A, a well-documented co-factor involved in liver fibrosis, on the pro-fibrogenic gene promoters during HSC activation. In addition, SRF directly regulated MRTF-A transcription in activated HSCs. More importantly, HSC conditional SRF knockout (CKO) mice developed a less robust pro-fibrogenic response in the liver in response to CCl4 injection and BDL compared to wild-type littermates. In conclusion, our data demonstrate that SRF may play an essential role in HSC activation and liver fibrosis. Key messages center dot SRF deficiency decelerates activation of hepatic stellate cells (HSCs) in vitro. center dot SRF epigenetically activates pro-fibrogenic transcription to promote HSC maturation. center dot SRF interacts with MRTF-A and contributes to MRTF-A transcription. center dot Conditional SRF deletion in HSCs attenuates BDL-induced liver fibrosis in mice. center dot Conditional SRF ablation in HSCs attenuates CCl4-induced liver fibrosis in mice.