An Update on Human Thyroid Hormone Receptors in Health and Disease: Chemistry, Physiology and Pathophysiology

Iodothyronines, the tetra- and tri-iodothyronines (T₄ and T₃), commonly known as thyroid hormones (THs), are secreted by thyroid glands. Thyroid hormones influence the growth and differentiation of every organ of the body via specific nuclear receptors (TRs), which belong to the nuclear receptor superfamily. Though thyroid glands secrete predominantly T₄ (which remains bound to its serum binding proteins), T₃ is the biologically active TH. Free T₄ enters the target cells through specific transporters and is converted into T₃ by cell-specific isoforms of cytoplasmic 5' deiodinase, which regulate the circulating T₃ levels and its availability for nuclear TRs in a tissue-specific manner. T₃ is then translocated to the nucleus, with the help of NADPH-dependent cytosolic transporter, where it binds to the monomers of TR subtypes (TRα and TRβ). Prior to the binding of T₃, TR monomer dimerizes with the 9-cis retinoic acid or retinoid X receptor (RXR) and the TR-RXR heterodimer, in association with corepressors, binds to specific TR response element (TRE) in the target genes. Upon T₃ binding to the TR monomer of the TR-RXR-TRE complex, corepressors get released paving way for the binding of coactivators, thereby inducing the transcription of T₃-responsive genes. Apart from the canonical nuclear signalling mechanism, membrane-mediated signalling by THs occurs through its interaction with plasma membrane integrin ανβ3. The impact of TH status and TR signalling on a broad range of genes makes studying its effect in vivo a difficult task. Studies on knock-in/out/mutant animal models and humans harboring several mutations of TR isoforms have helped explain various disorders of TH action, particularly the hypothyroid condition associated with the resistance to TH action. The aim of this review is to provide the readers with the information on THs biosynthesis along with the recent progress in TR signalling and its physiological impact on human health.