Circadian REV-ERBs repress E4bp4 to activate NAMPT-dependent NAD+ biosynthesis and sustain cardiac function

Pieterjan Dierickx, Kun Zhu, Bryce J. Carpenter, Chunjie Jiang, Marit W. Vermunt, Yang Xiao, Timothy S. Luongo, Tsunehisa Yamamoto, Íngrid Martí-Pàmies, Sobuj Mia, Mary Latimer, Abhinav Diwan, Juanjuan Zhao, Amy K. Hauck, Brianna Krusen, Hoang C.B. Nguyen, Gerd A. Blobel, Daniel P. Kelly, Liming Pei, Joseph A. BaurMartin E. Young, Mitchell A. Lazar

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


The heart is a highly metabolic organ that uses multiple energy sources to meet its demand for ATP production. Diurnal feeding–fasting cycles result in fluctuations in substrate availability, which, together with increased energetic demand during the active period, impose a need for rhythmic cardiac metabolism. The nuclear receptors REV-ERBα and REV-ERBβ are essential repressive components of the molecular circadian clock and major regulators of metabolism. To investigate their role in the heart, here we generated mice with cardiomyocyte (CM)-specific deletion of both Rev-erb genes (Nr1d1/2), which died prematurely due to dilated cardiomyopathy. Loss of REV-ERBs markedly downregulated expression of fatty acid-oxidation genes before overt pathology, which was mediated by induction of the transcriptional repressor E4BP4, a direct target of cardiac REV-ERBs. E4BP4 directly controls circadian expression of Nampt and its biosynthetic product NAD+ via distal cis regulatory elements. Thus, REV-ERB-mediated E4BP4 repression is required for Nampt expression and NAD+ production by the salvage pathway. Together, these results highlight the indispensable role of circadian REV-ERBs in cardiac gene expression, metabolic homeostasis and function.

Original languageEnglish
Pages (from-to)45-58
Number of pages14
JournalNature Cardiovascular Research
Issue number1
StatePublished - Jan 2022


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