Glucocorticoid Receptor Inhibits the Progression of Schistosomiasis Hepatic Fibrosis Through Inducing Circadian Clock Gene Per1

Abstract

Hepatic fibrosis is the leading cause of morbidity and mortality in schistosomiasis, and transcription factors (TF) may become potential therapeutic targets for this disease. Here, we found that a TF, NR3C1, was significantly downregulated in hepatic stellate cells (HSC), the effector cell of hepatic fibrosis, from mice infected with Schistosoma japonicum using RNA sequencing. Activation of NR3C1 using dexamethasone blocked HSC activation and hepatic fibrosis progression, while these effects were completely abolished upon specific deletion of NR3C1 in HSCs. Genome-wide binding site and transcriptome analyses suggested that Per1, a circadian clock gene, was under the direct control of NR3C1 through binding the glucocorticoid response elements, and it was responsible for the inhibitory effect of NR3C1 on HSC activation. Therefore, NR3C1 is a key TF in the activation of HSCs and a potential therapeutic target for hepatic schistosomiasis.

Keywords: circadian clock gene; glucocorticoid receptor; hepatic fibrosis; hepatic stellate cell; schistosomiasis.