SR9009 has REV-ERB-independent effects on cell proliferation and metabolism.

The nuclear receptors REV-ERBα and -β link circadian rhythms and metabolism. Like other nuclear receptors, REV-ERB activity can be regulated by ligands, including naturally occurring heme. A putative ligand, SR9009, has been reported to elicit a range of beneficial effects in healthy as well as diseased animal models and cell systems. However, the direct involvement of REV-ERBs in these effects of SR9009 has not been thoroughly assessed, as experiments were not performed in the complete absence of both proteins. Here, we report the generation of a mouse model for conditional genetic deletion of REV-ERBα and -β. We show that SR9009 can decrease cell viability, rewire cellular metabolism, and alter gene transcription in hepatocytes and embryonic stem cells lacking both REV-ERBα and -β. Thus, the effects of SR9009 cannot be used solely as surrogate for REV-ERB activity.