Thyroid Hormone Receptor Beta: Functions and Health Effects

Thyroid hormones regulate the body’s metabolism, growth, and development. Their effects are mediated by receptors that allow cells to respond to their signals. Thyroid Hormone Receptor Beta (TRβ) is a nuclear receptor that facilitates many actions of the active thyroid hormone, triiodothyronine (T3). It is one of two primary thyroid hormone receptors, working alongside Thyroid Hormone Receptor Alpha (TRα). TRβ has a specific role in overseeing processes within the liver, pituitary gland, and brain.

How Thyroid Hormone Receptor Beta Works

Thyroid Hormone Receptor Beta is a protein found within the cell nucleus, where it directly influences gene activity. It is a nuclear receptor, a type of transcription factor activated by hormones. In its default state, without the active thyroid hormone T3, TRβ binds to specific DNA sections called Thyroid Hormone Response Elements (TREs). This binding occurs with TRβ forming a heterodimer with another nuclear receptor, most commonly the Retinoid X Receptor (RXR).

When TRβ is bound to a TRE without T3, it actively suppresses the associated gene’s expression by recruiting proteins called corepressors. The arrival of T3 from the bloodstream into the nucleus changes this dynamic. T3 fits into a specific location on the TRβ protein called the ligand-binding domain.

The binding of T3 changes the three-dimensional shape of the TRβ protein. This shift causes the receptor to release corepressor proteins and recruit a new set of proteins known as coactivators. This new complex of T3, TRβ, RXR, and coactivators then initiates transcription, switching the target gene “on.” This mechanism provides precise, hormone-driven control over a cell’s genetic instructions.

Key Functions of TRβ in the Body

Thyroid Hormone Receptor Beta’s presence in the liver is significant for metabolic regulation. In this organ, TRβ activation drives cholesterol processing. It lowers low-density lipoprotein (LDL) cholesterol by increasing LDL receptors on liver cells, which pull LDL from the bloodstream. TRβ also contributes to bile acid synthesis and helps reduce the accumulation of triglycerides within the liver.

TRβ has a pronounced role within the pituitary gland, which governs the thyroid. It is a component of the body’s negative feedback system for thyroid hormone production. When blood levels of thyroid hormone are high, they activate TRβ in the pituitary. This signals the gland to reduce its secretion of Thyroid-Stimulating Hormone (TSH), which in turn signals the thyroid gland to produce less hormone.

TRβ also contributes to the development and function of the central nervous system. In the brain, it is involved in myelination, the formation of the protective sheath around nerve fibers. It also has a function in the development of the auditory system, and its proper action is needed for normal hearing. While TRα is more dominant in controlling heart rate and bone metabolism, TRβ’s roles in the liver and pituitary highlight their distinct functions.

When TRβ Goes Wrong: Associated Health Conditions

Genetic mutations in the THRB gene, which provides instructions for the TRβ protein, can cause health issues. The most documented is Resistance to Thyroid Hormone beta (RTHβ), a rare genetic disorder. In individuals with RTHβ, the receptors are non-functional, so target cells in the liver and pituitary cannot respond to thyroid hormone.

A distinctive laboratory profile for RTHβ shows high levels of circulating thyroid hormones (T4 and T3), yet the TSH level is not suppressed. TSH may be normal or slightly elevated because the pituitary’s TRβ receptors do not sense the high hormone levels, failing the negative feedback loop. This condition is inherited in an autosomal dominant pattern, so a person only needs one copy of the mutated gene to be affected.

The symptoms of RTHβ can vary widely among affected individuals. Common features include:

• A goiter (enlargement of the thyroid gland) from constant TSH stimulation.
• A persistently fast heart rate (tachycardia).
• Neurodevelopmental issues such as attention-deficit/hyperactivity disorder (ADHD) and learning disabilities.
• Hearing impairments, reflecting TRβ’s role in the auditory system.

TRβ as a Target for New Medicines

The functions of TRβ, particularly its effects on liver metabolism, have made it a target for drug development. The goal is to create selective TRβ agonists—medicines that activate TRβ without affecting TRα. This selectivity allows researchers to harness the benefits of thyroid hormone action in the liver while avoiding side effects in the heart and bones, which are more influenced by TRα.

This research focuses on treating metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe form, metabolic dysfunction-associated steatohepatitis (MASH). These conditions involve fat buildup in the liver, leading to inflammation and fibrosis. TRβ agonists can reduce liver fat, resolve inflammation, and reverse fibrosis by mimicking T3’s effects in the liver. An example is the drug Resmetirom, developed for the treatment of MASH.

These targeted therapies also help manage dyslipidemia, a condition of unhealthy lipid levels. By selectively activating TRβ in the liver, these drugs can lower LDL cholesterol and triglycerides. This approach avoids the risks of older, non-selective thyroid hormone analogs, which could cause cardiac arrhythmias and bone loss by activating TRα. TRβ-selective agonists represent a refined strategy for treating complex metabolic diseases.