Faculty Collaboration Database

Circadian REV-ERBs repress E4bp4 to activate NAMPT-dependent NAD⁺ biosynthesis and sustain cardiac function. Nat Cardiovasc Res 2022 Jan;1(1):45-58

Date

01/18/2022

Pubmed ID

35036997

Pubmed Central ID

PMC8754391

DOI

10.1038/s44161-021-00001-9

Scopus ID

2-s2.0-85135126993 (requires institutional sign-in at Scopus site)   64 Citations

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.

Author List

Dierickx P, Zhu K, Carpenter BJ, Jiang C, Vermunt MW, Xiao Y, Luongo TS, Yamamoto T, Martí-Pàmies Í, Mia S, Latimer M, Diwan A, Zhao J, Hauck AK, Krusen B, Nguyen HCB, Blobel GA, Kelly DP, Pei L, Baur JA, Young ME, Lazar MA

Author

Yang Xiao Assistant Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

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