Estrogen-related Receptor Assays

Background of Estrogen-related Receptor

Estrogen-related receptors (ERRs) are orphan nuclear receptors with undetermined endogenous ligands. As members of the nuclear receptor superfamily, ERRs present a tight structural relationship with ERα and ERβ. Similar to other nuclear receptors, ERRs consist of six conserved regions, A/B, C, D, and E/F domains. A/B domains possess ligand-independent transcriptional activation properties and allow their transcriptional activity to be regulated by post-translational modifications.

Fig.1 Structure of estrogen receptor α and the three estrogen-related receptors. Fig.1. Structure of estrogen receptor α and the three estrogen-related receptors. (Tang, 2021)

Distribution and Function of Estrogen-related Receptor

ERRs are widely expressed in various tissues, especially the kidney, heart, cerebellum, intestine, and skeletal muscle. Studies have shown that high-level expression of ERRα can be detected in breast tumors. The study of the structure and pathological function of the ERR orphan nuclear receptor family makes ERR a potential target for a variety of diseases, including osteoarthritis, breast cancer, and prostate cancer.

Subtypes and Mechanisms of Estrogen-related Receptor

Till now, there are three human estrogen-related receptors, including estrogen-related receptor alpha (ERRα), estrogen-related receptor beta (ERRβ), and estrogen-related receptor gamma (ERRγ).

Receptor	Gene	Mechanism	Agonists	Antagonists
Estrogen-related receptor alpha	ESRRA	ERRα interacts with estrogen and the transcription factor TFIIB by direct protein-protein contact. ERRα can modulate the activity of ERα in various tissues.	XCT 790	Bortezomib Carfilzomib Artemisinin
Estrogen-related receptor beta	ESRRB	Overexpression of ERRβ results in the suppression of cell proliferation in both androgen-sensitive and insensitive prostate cancer cells.	DY131 GSK 4716	Diethylstilbestrol
Estrogen-related receptor gamma	ESRRG	Overexpression of ERRγ results in the suppression of cell proliferation in both androgen-sensitive and insensitive prostate cancer cells. Bisphenol A functions as a xenoestrogen by binding strongly to ERRγ.	Diethylstilbestrol DY131 GSK 4716	4-hydroxytamoxifen

Published Data

Paper Title	Estrogen-related receptor alpha: an under-appreciated potential target for the treatment of metabolic diseases
Journal	International Journal of Molecular Sciences
Published	2020
Abstract	Studies have shown that ESRRA plays a key role in mitochondrial homeostasis, energy metabolism, adaptive thermogenesis, and adipogenesis. Under normal physiological conditions and energy- and nutritional-related stress, ESRRA can function in a variety of organizations. These properties make ESRRA a potential therapeutic target for metabolic disorders. ESRRA also plays a key role in TH-mediated fatty acid β-oxidation and increased mitochondrial turnover. So far, no synthetic agonists have been developed. Inhibition of ESRRA by inverse agonists may also be beneficial in specific stages of obesity, diabetes, and NAFLD, while agonists are useful in other stages. In animal experiments, systemic ESRRA knockout in mice provided some protection against DIO, so there may be differences between systemic and tissue-specific effects of ESRRA. In aging tissues, ESRRA expression is reduced, so agonists may be more effective in certain age groups of patients. Furthermore, since ESRRA activity is also regulated by post-translational modifications and co-regulation, combination therapy with drugs targeting other mechanisms or convergent/parallel metabolic pathways may lead to better outcomes.
Result	Estrogen-related receptor alpha (ESRRA) is an orphan nuclear receptor (NR) with the ability to affect cellular metabolism. Primarily expressed in metabolically active tissues, ESRRA can regulate the transcription of metabolic genes, especially those involved in mitochondrial turnover and autophagy. Furthermore, ESRRA activity has been well characterized in several types of cancer and some metabolic diseases. This small review focuses on the regulation of cellular metabolism and function by ESRRAs and their potential as therapeutic targets for metabolic disorders.

References

Tang, J.; et al. Estrogen-related receptors: novel potential regulators of osteoarthritis pathogenesis. Molecular Medicine. 2021, 27(1): 1-12.
Tripathi, M.; et al. Estrogen-related receptor alpha: an under-appreciated potential target for the treatment of metabolic diseases. International Journal of Molecular Sciences. 2020, 21(5): 1645.

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