br Roles of ERR in Physiology and Disease br Concluding
Roles of ERRγ in Physiology and Disease
Concluding Remarks and Future Perspectives Over the last decade, the generation of tissue-specific ERRγ transgenic or knockout mice and the use of synthetic ligands have rapidly advanced our understanding of the roles of ERRγ in cellular functions, although several questions remain unanswered (see Outstanding Questions). Given its diverse functions, it can be argued that ERRγ behaves as both a friend and a foe. On the one hand, it is critical for mitochondrial biogenesis and respiration in response to cellular stress or environmental cues. Mice lacking ERRγ die within the first week of life due to mitochondrial dysfunction. Due to its involvement in OxPhos, it is essential for the function of organs with high-energy demands such as the heart, skeletal muscle, and brain. On the other hand, ERRγ associates with different pathological conditions, including type 2 diabetes and alcoholic liver disease, in which the pharmacological inhibition of ERRγ restores glucose normalcy with enhanced insulin-sensitivity in mice. These dual functions of ERRγ raise interest in understanding its roles in different tissues and warrant additional research. ERRγ has emerged as a key transcriptional regulator of pathways crucial in the regulation of endocrine and metabolic functions.
Acknowledgments We extend our apology for not citing other relevant publications here owing to space restrictions. We thank Robert A. Harris for critical reading and comments. This work is supported by National Creative Research Initiatives Grant (20110018305 to H.S.C.) and Basic Science Research Program (NRF-2015R1C1A1A01051513 to D.K.K) through the National Research Foundation of Korea (NRF) funded by the Korean government (Ministry of Science, ICT & Future Planning).
Introduction Nuclear receptors are ligand-dependent transcription factors that regulate gene expression in response to small molecule ligands. Orphan members of the nuclear receptor superfamily, which have no identified endogenous ligand, are involved in regulation of many aspects of cellular metabolism including mitochondrial energetics as well as cholesterol, bile BDS I and glucose metabolism. Therefore, they represent an important class of molecular targets for the treatment or prevention of a wide array of diseases. The estrogen-related receptor (ERR) orphan receptor subfamily comprises three subtypes, ERRα, ERRβ, and ERRγ. The ERRs are first orphan nuclear receptors identified based on their structural similarity with the estrogen receptor (ER). Although it was originally believed that the developmental and physiological roles of ERRs were quite distinct from those of the classic ERs, recent studies have shown that in some contexts ERRs share target genes, coregulatory proteins, ligands, and sites of action with the ERs. Such evidence has been extensively reviewed. ERRs play an important role in the transcriptional control of metabolic genes involved in the generation and utilization of cellular energy. Thus, ERRs might present a therapeutic target for the prevention of obesity and type 2 diabetes. Although the ERRα, ERRβ, and ERRγ isoforms all share considerable amino acid sequence identity with ERs in both the DNA binding domain (DBD) and ligand binding domain (LBD), they do not respond to natural estrogens, such as E2 (17β-estradiol, Fig. 1).6, 7, 8 ERRs are primarily expressed in the heart, skeletal muscle, brain, kidney, pancreas, placenta, and liver and are predicted to have significant differences in their ligand-binding preferences.9, 10 However, the mechanisms governing target gene selectivity of the individual ERR isoforms are not well understood. ERRα regulates genes involved in mitochondrial biogenesis (Gabpa/NRF2a, Tfam), fission/fusion (Mfn1 and 2, Opa1) as well as metabolic enzymes of β-oxidation (Acadm) and ETC/oxphos (Sdha, Cytc) pathways in conjunction with PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1α), a master regulator of lipid and glucose homeostasis. In cancer cells ERRα also regulates cellular metabolism as well as genes relevant to proliferation and metastasis and is associated with poor prognosis in human breast cancer.12, 13 ERRα expression correlates HER2 status and has been shown to mediate the effects of growth factor signaling on metabolic reprogramming that is required for the development of chemoresistance.14, 15 Thus, ERRα is considered a potential drug target with potential to treat metabolic disorders and cancer.16, 17, 18