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Rev-erb, a Heme Sensor That Coordinates Metabolic and Circadian Pathways
Lei Yin,1
Nan Wu,1
Joshua C. Curtin,1
Mohammed Qatanani,1
Nava R. Szwergold,1
Robert A. Reid,2
Gregory M. Waitt,2
Derek J. Parks,3
Kenneth H. Pearce,3
G. Bruce Wisely,3
Mitchell A. Lazar1*
Abstract:
The circadian clock temporally coordinates metabolic homeostasisin mammals. Central to this is heme, an iron-containing porphyrinthat serves as prosthetic group for enzymes involved in oxidativemetabolism as well as transcription factors that regulate circadianrhythmicity. The circadian factor that integrates this dualfunction of heme is not known. We show that heme binds reversiblyto the orphan nuclear receptor Rev-erb, a critical negativecomponent of the circadian core clock, and regulates its interactionwith a nuclear receptor corepressor complex. Furthermore, hemesuppresses hepatic gluconeogenic gene expression and glucoseoutput through Rev-erb–mediated gene repression. Thus,Rev-erb serves as a heme sensor that coordinates the cellularclock, glucose homeostasis, and energy metabolism.
1 Division of Endocrinology, Diabetes, and Metabolism; Department of Medicine; and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. 2 Department of Computational and Structural Chemistry, Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709–3398, USA. 3 Department of Biological Reagents and Assay Development, Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709–3398, USA.
* To whom correspondence should be addressed. E-mail: lazar{at}mail.med.upenn.edu
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Nuclear Hormone Receptors for Heme: REV-ERB{alpha} and REV-ERB{beta} Are Ligand-Regulated Components of the Mammalian Clock.
, a Heme Sensor That Coordinates Metabolic and Circadian Pathways
, a critical negative component of the circadian core clock, and regulates its interaction with a nuclear receptor corepressor complex. Furthermore, heme suppresses hepatic gluconeogenic gene expression and glucose output through Rev-erb
