Nuclear Receptors and the Hidden Language of the Metabolome

• Published in: Cells (Basel, Switzerland) Vol. 13; no. 15; p. 1284
• Main Authors: Chen, Yujie, Anderson, Matthew Tom, Payne, Nathaniel, Santori, Fabio R, Ivanova, Natalia B
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.08.2024
• Subjects: Amino acids; Animals; Bile; Biosynthesis; Coevolution; DNA binding proteins; Enzymes; Estrogens; evolution; Fatty acids; Gene regulation; Hormones; Humans; Hypotheses; Ligands; Medical innovations; Metabolism; Metabolites; Metabolome; Nematodes; nuclear receptor; Nuclear receptors; Physiological aspects; Physiology; Receptors, Cytoplasmic and Nuclear - metabolism; Regenerative medicine; regulation; Steroid hormones; Steroids; Sterols; Transcription factors; ligands; nuclear receptor; evolution; regulation; hormones; metabolites
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13151284

Nuclear hormone receptors (NHRs) are a family of ligand-regulated transcription factors that control key aspects of development and physiology. The regulation of NHRs by ligands derived from metabolism or diet makes them excellent pharmacological targets, and the mechanistic understanding of how NHRs interact with their ligands to regulate downstream gene networks, along with the identification of ligands for orphan NHRs, could enable innovative approaches for cellular engineering, disease modeling and regenerative medicine. We review recent discoveries in the identification of physiologic ligands for NHRs. We propose new models of ligand-receptor co-evolution, the emergence of hormonal function and models of regulation of NHR specificity and activity via one-ligand and two-ligand models as well as feedback loops. Lastly, we discuss limitations on the processes for the identification of physiologic NHR ligands and emerging new methodologies that could be used to identify the natural ligands for the remaining 17 orphan NHRs in the human genome.