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Originally published in Science Express on 15 November 2007
Science 14 December 2007:
Vol. 318. no. 5857, pp. 1786 - 1789
DOI: 10.1126/science.1150179
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Reports

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. Lazar1*

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.

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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