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

The estrogen-related receptor alpha (ERRalpha) is an orphan nuclear receptor (ONR) that by binding to DNA sites controls gene expression in association with coactivators and corepressors. ERRalpha was the first ONR to be identified; however, its natural endogenous ligand(s) is still unknown. ERRalpha 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 ERRalpha has been detected in several tissues, including those with high metabolic activities and energy demand. Presently, the control of energy balance by ERRalpha seems to be its prime role. The nonavailability of endogenous ligand for ERRalpha has not impeded the study of its functions. In fact, most of the present knowledge of the biological roles of ERRalpha has evolved from in-depth biochemical, overexpression, genomic, including functional genomics studies, and also through the generation of intact ERRalpha knockout (null) mice. Interestingly, over the past few years, growing evidence suggests interplay between ERRalpha and various human metabolic diseases such as diabetes, obesity, and heart disease. Also, there are strong indications of the involvement of ERRalpha in cancer initiation and progression. Interestingly, this makes ERRalpha 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 ERRalpha in metabolism and other biological functions, including its role in human diseases.