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.