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

Proc Natl Acad Sci U S A. 2019 Jun 18;116(25):12147-12152. doi: 10.1073/pnas.1904226116. Epub 2019 May 24.


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.

Keywords: REV-ERB; SR9009; circadian rhythms; ligand; specificity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects*
  • Cell Respiration / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Gene Expression / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / drug effects*
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / physiology
  • Pyrrolidines / pharmacology*
  • Receptors, Cytoplasmic and Nuclear / drug effects*
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Repressor Proteins / drug effects*
  • Repressor Proteins / physiology
  • Thiophenes / pharmacology*


  • Nr1d2 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Pyrrolidines
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins
  • SR9009
  • Thiophenes