TY - JOUR
T1 - Circadian REV-ERBs repress E4bp4 to activate NAMPT-dependent NAD+ biosynthesis and sustain cardiac function
AU - Dierickx, Pieterjan
AU - Zhu, Kun
AU - Carpenter, Bryce J.
AU - Jiang, Chunjie
AU - Vermunt, Marit W.
AU - Xiao, Yang
AU - Luongo, Timothy S.
AU - Yamamoto, Tsunehisa
AU - Martí-Pàmies, Íngrid
AU - Mia, Sobuj
AU - Latimer, Mary
AU - Diwan, Abhinav
AU - Zhao, Juanjuan
AU - Hauck, Amy K.
AU - Krusen, Brianna
AU - Nguyen, Hoang C.B.
AU - Blobel, Gerd A.
AU - Kelly, Daniel P.
AU - Pei, Liming
AU - Baur, Joseph A.
AU - Young, Martin E.
AU - Lazar, Mitchell A.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85135126993&partnerID=8YFLogxK
U2 - 10.1038/s44161-021-00001-9
DO - 10.1038/s44161-021-00001-9
M3 - Article
C2 - 35036997
AN - SCOPUS:85135126993
SN - 2731-0590
VL - 1
SP - 45
EP - 58
JO - Nature Cardiovascular Research
JF - Nature Cardiovascular Research
IS - 1
ER -