Health & Medical Endocrine disease

Causes of Reduced Sensitivity to Thyroid Hormone

Causes of Reduced Sensitivity to Thyroid Hormone

Regulation of TH Bioactivity

Serum TH levels are principally regulated by the hypothalamus–pituitary–thyroid (HPT) axis. The hypothalamus produces thyrotrophin releasing hormone (TRH), which stimulates the pituitary to produce thyroid-stimulating hormone (TSH). TSH acts on the thyroid gland to synthesize TH. The thyroid secretes predominantly the prohormone T4 and to a lesser extent the bioactive hormone T3.

TH bioactivity and action are regulated at the cellular level (Fig. 1). Most actions of TH are initiated by binding of T3 to its nuclear T3 receptors (TRs), located on T3 response elements (TREs) in the promoter region of target genes. Binding of T3 results in a change in the interaction of TRs with co-activator and corepressor proteins and consequently in an altered expression of the target genes. Different TR isoforms are encoded by two genes: THRA and THRB. TRα1 is the predominant TR receptor isoform expressed in brain, bone and heart, whereas TRβ1 is considered the major isoform in liver, kidney and thyroid. Through alternative exon usage, TRβ2 differs from TRβ1 at the N-terminus and displays a more restricted expression pattern (retina, cochlea, pituitary).

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Figure 1.

Model of TH regulation at the cellular level. Transporters are required for uptake and release of T4 and T3. MCT8 is prototypic for cellular T3 and T4 transport. Three deiodinases are involved in activation or inactivation of TH. D1 is mainly involved in TH regulation in serum and therefore is not shown in the figure. D2 and D3 are important for local TH regulation. D2 converts T4 to bioactive T3, whereas D3 degrades T3 to 3,3'-T2. Insertion of the selenocysteine into the deiodinases requires SBP2. Ultimately, T3 binds to its nuclear receptors (TRs) and modulates gene expression of T3-target genes.

Intracellular T3 levels are governed by intracellular deiodinases and TH transporters at the plasma membrane. Three deiodinating enzymes (D1–3) have been identified, which catalyse the activation of T4 to T3 or the inactivation of T4 to 3,3',5'-triiodothyronine (reverse T3, rT3) and of T3 to 3,3'-diiodothyronine (3,3'-T2). D1 is highly expressed in liver, kidney and thyroid and is considered important for serum T3 production as well as for clearance of serum rT3. D2 is localized particularly in brain, pituitary, brown adipose tissue, thyroid and skeletal muscle. It has been firmly established that D2 is crucial for local production of T3 in different tissues. D3 is an inactivating enzyme catalysing degradation of T3 and T4. D3 is mainly expressed in foetal tissues. In adult life, D3 expression is limited to the brain and skin, but can be reactivated in other tissues under pathological conditions. Recent studies have established that intracellular TH signalling can be largely modified by deiodination without affecting circulating TH levels, thereby modulating processes such as differentiation and regeneration.

Because action and deiodination of TH take place intracellularly, transport of the hormone across the plasma membrane is required. Although many transporters accept TH as a ligand, only a few have been shown to be specific TH transporters. Monocarboxylate transporter 8 (MCT8, SLC16A2) has been shown to specifically transport the iodothyronines T4, T3, rT3 and T2. The highly homologous MCT10 (SLC16A10) was initially designated as a T-type aromatic amino acid transporter, but has later been shown to transport TH, with a preference for T3 over T4. Both MCT8 and MCT10 are widely expressed. The organic anion-transporting polypeptide 1C1 (OATP1C1) is importantly expressed in brain and transports T4. Possibly, other as-yet-unknown specific TH transporters are important for human physiology.

The last decade has witnessed the discovery of several novel syndromes of reduced sensitivity to TH, related to dysfunction in TH transport, deiodination and receptor function.

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