Nuclear Receptors, RXR, and the Big Bang

Abstract

Isolation of genes encoding the receptors for steroids, retinoids, vitamin D, and thyroid hormone and their structural and functional analysis revealed an evolutionarily conserved template for nuclear hormone receptors. This discovery sparked identification of numerous genes encoding related proteins, termed orphan receptors. Characterization of these orphan receptors and, in particular, of the retinoid X receptor (RXR) positioned nuclear receptors at the epicenter of the "Big Bang" of molecular endocrinology. This Review provides a personal perspective on nuclear receptors and explores their integrated and coordinated signaling networks that are essential for multicellular life, highlighting the RXR heterodimer and its associated ligands and transcriptional mechanism.

Figure 1. Nuclear Receptor Discovery Timeline

Schematic timeline showing landmark discoveries in the nuclear receptor field over the last three decades. The entries start from the cloning of the first steroid hormone receptor cDNA to more recent ‘omic’ findings. Inset on the right shows total publications for all nuclear receptors as well as that for RXR and heterodimer partners over time.

Figure 2. The RXR Big Bang

The cloning of the RXRs as receptors for 9-cis retinoic acid initiated an expanding wave of discoveries that included: 1) the ability of RXRs to heterodimerize with numerous other nuclear receptors as a mechanism to control gene-specific transcription; 2) the characterization of dietary lipid metabolites (i.e., oxysterols, bile acids, fatty acids, and xenobiotic lipids) as ligands for RXR-partnered orphan receptors; 3) the elucidation of novel endocrine and paracrine signaling pathways mediated by RXR heterodimers, including the fibroblast growth factors 1, 19 and 21; and 4) the role of these receptors in diverse developmental and metabolic pathways. BMR, basal metabolic rate

Figure 3. The 3-4-5 rule

Receptors bind DNA as monomers to a single hexad motif, as homodimers to a palindrome of two hexad motifs, or as RXR heterodimers to a tandem repeat of the hexad motif. Heterodimers bind AGGTCA direct repeats (DRs) spaced by 3 (DR3; vitamin D response element), 4 (DR4; thyroid response element) or 5 (DR5; retinoic acid response element) nucleotides as described in the 3-4-5 rule.

Fig 4. Metabolic homeostasis & the energy vector

The figure illustrates that nutrients, such as sugar and fat, enter the body and are processed in a highly vectorial fashion. Vector 1: The gallbladder, pancreas and intestine are the most important digestive organs in the body. Detergent properties of bile acids both solubilize lipids to promote lipid absorption and by activating FXR to transiently induce 100s of genes for nutrient transport and suppression of microbial activity along with the release of FGF19 as a hormonal signal to the liver. In the liver, PPARα is activated to break down fatty acids and induce FGF21 as a hormonal signal to adipose (and other tissues in the body). LXR induces Cyp7a1 to convert cholesterol into bile acid and SREBP-1c activation for fatty acid synthesis. Vector 2: PPARδ activation during exercise triggers production of sugar and fat in the liver for delivery to muscle for both glycolytic and oxidative metabolism. Vector 3: unconsumed energy is sent to fat where under the control of the PPARγ-FGF1 and -FGF21 axis, nutrients are stored in adipose tissue. Vector 4: In response to demand, nutrients stored in visceral fat are sent to muscle or other tissues.