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

Nat Cardiovasc Res. 2022 Jan;1(1):45-58. doi: 10.1038/s44161-021-00001-9. Epub 2021 Dec 23.

Abstract

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 substrate availability fluctuations which, together with increased energetic demand during the active period, impose a need for rhythmic cardiac metabolism. The nuclear receptors REV-ERBα and β 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-erbs, which died prematurely due to dilated cardiomyopathy. Loss of Rev-erbs markedly downregulated fatty acid oxidation genes prior to 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.

Publication types

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

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Cells, Cultured
  • Circadian Clocks / genetics
  • Circadian Clocks / physiology
  • Circadian Rhythm* / physiology
  • Cytokines* / metabolism
  • Gene Expression Regulation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocytes, Cardiac* / metabolism
  • NAD* / biosynthesis
  • NAD* / metabolism
  • Nicotinamide Phosphoribosyltransferase* / genetics
  • Nicotinamide Phosphoribosyltransferase* / metabolism
  • Nuclear Receptor Subfamily 1, Group D, Member 1* / genetics
  • Nuclear Receptor Subfamily 1, Group D, Member 1* / metabolism
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins

Substances

  • Basic-Leucine Zipper Transcription Factors
  • Cytokines
  • NAD
  • Nfil3 protein, mouse
  • Nicotinamide Phosphoribosyltransferase
  • nicotinamide phosphoribosyltransferase, mouse
  • Nr1d1 protein, mouse
  • Nr1d2 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Receptors, Cytoplasmic and Nuclear
  • Repressor Proteins