Abstract
Autophagy and cellular senescence are stress responses essential for homeostasis. Therefore, they may represent new pharmacologic targets for drug development to treat diseases. In this study, we sought to evaluate the effect of dihydroartemisinin (DHA) on senescence of activated hepatic stellate cells (HSCs), and to further elucidate the underlying mechanisms. We found that DHA treatment induced the accumulation of senescent activated HSCs in rat fibrotic liver, and promoted the expression of senescence markers p53, p16, p21 and Hmga1 in cell model. Importantly, our study identified the transcription factor GATA6 as an upstream molecule in the facilitation of DHA-induced HSC senescence. GATA6 accumulation promoted DHA-induced p53 and p16 upregulation, and contributed to HSC senescence. By contrast, siRNA-mediated knockdown of GATA6 dramatically abolished DHA-induced upregulation of p53 and p16, and in turn inhibited HSC senescence. Interestingly, DHA also appeared to increase autophagosome generation and autophagic flux in activated HSCs, which was underlying mechanism for DHA-induced GATA6 accumulation. Autophagy depletion impaired GATA6 accumulation, while autophagy induction showed a synergistic effect with DHA. Attractively, p62 was found to act as a negative regulator of GATA6 accumulation. Treatment of cultured HSCs with various autophagy inhibitors, led to an inhibition of DHA-induced p62 degradation, and in turn, prevented DHA-induced GATA6 accumulation and HSC senescence. Overall, these results provide novel implications to reveal the molecular mechanism of DHA-induced senescence, by which points to the possibility of using DHA based proautophagic drugs for the treatment of liver fibrosis.
Highlights
Liver fibrosis is a reversible wound-healing response following liver injury, and its end-stage cirrhosis is responsible for high morbidity and mortality worldwide.[1,2,3] Liver transplantation is the only treatment available for patients with advanced stages of liver fibrosis.[4,5,6] new therapeutic agents and strategies are needed for the management of this disease.[7,8]
We found that DHA could induce senescence of activated hepatic stellate cells (HSCs) to alleviate liver fibrosis via autophagydependent GATA6 accumulation
To investigate the mechanisms underlying the protective effects of DHA, we proposed that DHA might induce senescence of activated HSCs to limit liver fibrosis
Summary
Liver fibrosis is a reversible wound-healing response following liver injury, and its end-stage cirrhosis is responsible for high morbidity and mortality worldwide.[1,2,3] Liver transplantation is the only treatment available for patients with advanced stages of liver fibrosis.[4,5,6] new therapeutic agents and strategies are needed for the management of this disease.[7,8]. Previous studies[21,22] have reported that p53 can lead to cell cycle arrest, DNA repair and apoptosis predominantly when it becomes transcriptionally active in response to DNA damage, oncogene activation and hypoxia. Retinoblastoma 1 (pRb) inactivation mediated by p16 is known to ensure durable cell cycle arrest, but is unlikely to be regulated by a canonical DNA damage response.[23] Attractively, it is interesting to explore the mechanism underlying the induction and maintenance of cell senescence in liver fibrosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
