The estrogen-related receptor alpha: the oldest, yet an energetic orphan with robust biological functions

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Abstract
The estrogen-related receptor alpha (ERRα) is an orphan nuclear receptor (ONR) that by binding to DNA sites controls gene expression in association with coactivators and corepressors. ERRα was the first ONR to be identified; however, its natural endogenous ligand(s) is still unknown. ERRα by acting as a transcription factor has been shown to regulate a large array of genes, thereby controlling numerous metabolic pathways and other biological functions in animals. Of late, the expression of ERRα has been detected in several tissues, including those with high metabolic activities and energy demand. Presently, the control of energy balance by ERRα seems to be its prime role. The nonavailability of endogenous ligand for ERRα has not impeded the study of its functions. In fact, most of the present knowledge of the biological roles of ERRα has evolved from in-depth biochemical, overexpression, genomic, including functional genomics studies, and also through the generation of intact ERRα knockout (null) mice. Interestingly, over the past few years, growing evidence suggests interplay between ERRα and various human metabolic diseases such as diabetes, obesity, and heart disease. Also, there are strong indications of the involvement of ERRα in cancer initiation and progression. Interestingly, this makes ERRα a suitable, direct target for pharmacological intervention in treating such diseases. This review focuses on the overall developments and recent advances in understanding the role of ERRα in metabolism and other biological functions, including its role in human diseases.

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