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Published Online November 15, 2007
Science DOI: 10.1126/science.1150179

Reports

Submitted on September 6, 2007
Accepted on September 28, 2007

Rev-erb{alpha}, 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. Lazar 1*

1 Division of Endocrinology, Diabetes, and Metabolism; Department of Medicine; and The 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, North Carolina 27709-3398, USA.
3 Department of Biological Reagents and Assay Development, Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709-3398, USA.

* To whom correspondence should be addressed.
Mitchell A. Lazar , E-mail: lazar{at}mail.med.upenn.edu

The circadian clock temporally coordinates metabolic homeostasis in mammals. Central to this is heme, an iron-containing porphyrin that serves as prosthetic group for enzymes involved in oxidative metabolism as well as transcription factors that regulate circadian rhythmicity. The circadian factor that integrates this dual function of heme is not known. We show that heme binds reversibly to the orphan nuclear receptor Rev-erb{alpha}, 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{alpha}-mediated gene repression. Thus Rev-erb{alpha} serves as a heme sensor that coordinates the cellular clock, glucose homeostasis, and energy metabolism.


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