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

Mice with cardiomyocyte-specific deletion of REV-ERBα and β died prematurely due to dilated cardiomyopathy.

• Loss of REV-ERBα and β led to significant downregulation of genes involved in fatty acid oxidation before any visible heart disease appeared.
• The downregulation of these genes was linked to the increased expression of a transcriptional repressor called E4BP4.
• E4BP4 is a direct target of REV-ERBs and is crucial for regulating the circadian expression of genes related to NAD production.
• REV-ERB-mediated repression of E4BP4 is necessary for maintaining proper expression of NAD via the salvage pathway.
• These findings indicate that circadian REV-ERBs play a critical role in cardiac gene expression and metabolic stability.

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