期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 25, 页码 12147-12152出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1904226116
关键词
REV-ERB; circadian rhythms; SR9009; ligand; specificity
资金
- NIH [R01 DK45586, F30 DK104513]
- JPB Foundation
- Netherlands Heart Institute postdoctoral fellowship
- American Diabetes Association [1-18-PDF-126]
The nuclear receptors REV-ERB alpha and -beta 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-ERB alpha and -beta. We show that SR9009 can decrease cell viability, rewire cellular metabolism, and alter gene transcription in hepatocytes and embryonic stem cells lacking both REV-ERB alpha and -beta. Thus, the effects of SR9009 cannot be used solely as surrogate for REV-ERB activity.
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