Time-dependent effect of REV-ERBα agonist SR9009 on nonalcoholic steatohepatitis and gut microbiota in mice

The circadian clock is involved in the pathogenesis of nonalcoholic steatohepatitis (NASH), and the target pathways of many NASH candidate drugs are controlled by the circadian clock. However, the application of chronopharmacology in NASH is little considered currently. Here, the time-dependent effect of REV-ERBa agonist SR9009 on diet-induced NASH and microbiota was investigated. C57BL/6J mice were fed a high-cholesterol and high-fat diet (CL) for 12 weeks to induce NASH and then treated with SR9009 either at Zeitgeber time 0 (ZT0) or ZT12 for another 6 weeks. Pharmacological activation of REV-ERBa by SR9009 alleviated hepatic steatosis, insulin resistance, liver inflammation, and fibrosis in CL diet-induced NASH mice. These effects were accompanied by improved gut barrier function and altered microbial composition and function in NASH mice, and the effect tended to be stronger when SR9009 was injected at ZT0. Moreover, SR9009 treatment at different time points resulted in a marked difference in the composition of the microbiota, with a stronger effect on the enrichment of beneficial bacteria and the diminishment of harmful bacteria when SR9009 was administrated at ZT0. Therefore, the time-dependent effect of REV-ERBa agonist on NASH was partly associated with the microbiota, highlighting the potential role of microbiota in the chronopharmacology of NASH and the possibility of discovering new therapeutic strategies for NASH.

Automated summary

The time-dependent effect of REV-ERBa agonist SR9009 on diet-induced nonalcoholic steatohepatitis (NASH) and microbiota was investigated in this study. Pharmacological activation of REV-ERBa alleviated hepatic steatosis, insulin resistance, liver inflammation, and fibrosis in NASH mice, accompanied by improved gut barrier function and altered microbial composition and function. The timing of SR9009 administration also affected the composition of the microbiota, with greater effects on beneficial bacteria enrichment and harmful bacteria reduction when administered at Zeitgeber time 0 (ZT0). These findings highlight the potential role of microbiota in the chronopharmacology of NASH and the possibility of discovering new therapeutic strategies.