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  • br Acknowledgements Professor Olli A J nne

    2020-09-19


    Acknowledgements Professor Olli A. Jänne is warmly thanked for support cyproheptadine hcl and for providing excellent research facilities. Professor Patrik Finne is acknowledged for his help with statistical analyses. Drs Ronald Evans, Vincent Giguère, Jorma Palvimo, Malcolm Parker, and Anastasia Kralli are acknowledged for providing plasmids. This work was supported by grants from Research Council for Health/Academy of Finland, Emil Aaltonen Foundation, Finnish Cultural Foundation, Farmos Science and Research Foundation, Finnish Medical Foundation, Päivikki and Sakari Sohlberg Foundation, and Research Foundation of the University of Helsinki. Disclosure: The authors have nothing to disclose.
    Introduction The nuclear receptor (NR) superfamily is a large group of ligand-dependent transcription factors that regulate the cyproheptadine hcl of genes involved in development, homeostasis, and metabolism. However, there are a few orphan NRs, for which endogenous ligands have not yet been identified. The estrogen-related receptor (ERR) subfamily consists of three members, ERRα (NR3B1), ERRβ (NR3B2), and ERRγ (NR3B3), all of which are orphans. ERRα and ERRβ, which were identified before ERRγ, have been extensively studied.2, 3, 4 However, the role of ERRγ is not well understood, because ERRγ-null mice are not viable after birth. Recently, the generation of tissue-specific ERRγ knockout mice, gain- and loss-of-function studies, and the use of small synthetic ligands to modulate the transcriptional activity of ERRγ have allowed for rapid advances in our understanding of the metabolic functions of ERRγ in various tissues, such as the heart, muscle, pancreas, and liver. Indeed, it has been shown that ERRγ plays critical roles in multiple metabolic processes in the liver, including the regulation of glucose, lipid, alcohol, and iron metabolism, by modulating the expression of specific genes involved in endocrine and metabolic processes. Furthermore, abnormal regulation of ERRγ is associated with the pathogenesis of metabolic diseases. Interestingly, ERRγ has also been implicated in hepatocellular carcinoma, because it regulates the expression of microRNAs or deoxyribonucleic acid (DNA) methyltransferase.,
    ERRγ: Background ERRγ was first identified through its linkage with a critical region of Usher syndrome type IIa, and then as a protein that functionally interacts with the NR coactivator glucocorticoid receptor-interacting protein (GRIP)-1., It is primarily expressed in key metabolic tissues, such as the muscle, heart, brain, liver, and adipose tissue. ERRγ contains the typical structural features of the NRs (Fig. 1A), including a poorly conserved N-terminal domain containing an activation function (AF)-1 domain, a central zinc finger DNA-binding domain (DBD) that binds to the ERR response element (ERRE; TCAAGGTCA), and a C-terminal ligand-binding domain (LBD) that contains an AF-2 domain, which interacts with coactivators such as GRIP-1 and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and corepressors such as small heterodimer partner (SHP), dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1), and small heterodimer partner-interacting leucine zipper protein (SMILE) (Fig. 1B).10, 11, 12, 13, 14 As ERR isoforms have a highly conserved DBD, and their transcriptional activities rely on cooperation with similar coactivator and corepressor proteins, the transcriptional and physiological outcomes of ERRγ signaling are similar to the outcomes of ERRα and ERRβ signaling in several tissues where they are co-expressed, including the heart, kidney, stomach, and skeletal muscle.,15, 16, 17, 18, 19 However, ERRγ can also regulate genes that are important in various metabolic processes in the liver, independently of the other two isoforms.20, 21, 22, 23 Interestingly, the transcriptional activity of the ERRs depends on their ability to bind to the ERRE as monomers, as homodimers, or as heterodimers comprised of two distinct ERR isoforms, suggesting that the mode of ERRγ binding to its target gene promoters may affect the transcriptional and physiological outcomes in a cell- or tissue-specific manner.,24, 25, 26, 27