The nuclear receptors REV-ERBα (encoded by NR1D1) and REV-ERBβ (NR1D2) have remained orphans owing to the lack of identified physiological ligands. Here we show that heme is a physiological ligand of both receptors. Heme associates with the ligand-binding domains of the REV-ERB receptors with a 1:1 stoichiometry and enhances the thermal stability of the proteins. Results from experiments of heme depletion in mammalian cells indicate that heme binding to REV-ERB causes the recruitment of the co-repressor NCoR, leading to repression of target genes including BMAL1 (official symbol ARNTL), an essential component of the circadian oscillator. Heme extends the known types of ligands used by the human nuclear receptor family beyond the endocrine hormones and dietary lipids described so far. Our results further indicate that heme regulation of REV-ERBs may link the control of metabolism and the mammalian clock.

/pdf/identification-of-heme-as-the-ligand-for-the-orphan-nuclear-1k2ouc2bq0.pdf

Identification of heme as the ligand for the orphan nuclear receptors REV-ERBα and REV-ERBβ

This Review highlights recent progress in the development of ligands to target two classes of nuclear receptors — the REV-ERBs and retinoic acid receptor-related orphan receptors (RORs) — and describes how such ligands might be useful for treating disorders related to metabolism, immune function and the circadian rhythm.

/pdf/rev-erb-and-ror-nuclear-receptors-as-drug-targets-1le1hutul1.pdf

REV-ERB and ROR nuclear receptors as drug targets

The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-α is highly expressed in oxidative skeletal muscle and that its deficiency in muscle leads to reduced mitochondrial content and oxidative function, as well as upregulation of autophagy. These cellular effects resulted in both impaired mitochondrial biogenesis and increased clearance of this organelle, leading to compromised exercise capacity. On a molecular level, Rev-erb-α deficiency resulted in deactivation of the Lkb1-Ampk-Sirt1-Ppargc-1α signaling pathway. These effects were recapitulated in isolated fibers and in muscle cells after knockdown of the gene encoding Rev-erb-α, Nr1d1. In complementary experiments, Rev-erb-α overexpression in vitro increased the number of mitochondria and improved respiratory capacity, whereas muscle overexpression or pharmacological activation of Rev-erb-α in vivo increased exercise capacity. This study identifies Rev-erb-α as a pharmacological target that improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function.

/pdf/rev-erb-a-modulates-skeletal-muscle-oxidative-capacity-by-x3f65frk6o.pdf

Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy.

https://www.gastrojournal.org/article/S0016-5085(08)00855-X/pdf

Regulation of Bile Acid Synthesis by the Nuclear Receptor Rev-erbα

Circadian control depends on oscillating transcription factors, master switches synchronized by stimuli such as light and feeding Recent studies show that altering circadian rhythmicity also results in pathophysiological changes resembling the metabolic syndrome

When the Clock stops ticking, metabolic syndrome explodes

10.1074/jbc.M304664200 Access the most updated version of this article at doi: . JBC Affinity Sites Find articles, minireviews, Reflections and Classics on similar topics on the Alerts: When a correction for this article is posted • When this article is cited • to choose from all of JBC's e-mail alerts Click here http://www.jbc.org/content/278/39/37672.full.html#ref-list-1 This article cites 57 references, 38 of which can be accessed free at

The Orphan Nuclear Receptor Rev-Erb Is a Peroxisome Proliferator-activated Receptor (PPAR) Target Gene and Promotes PPAR -induced Adipocyte Differentiation*

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The Orphan Nuclear Receptor Rev-Erb Is a Peroxisome Proliferator-activated Receptor (PPAR) Target Gene and Promotes PPAR -induced Adipocyte Differentiation*