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  • Although several genomic technologies including the generati


    Although several genomic technologies, including the generation of ERRγ-specific knockout mice, have revealed that ERRγ plays a pivotal role in cellular bioenergetics [1], its involvement in other metabolic pathways has been appreciated only recently. Therefore, we highlight recent findings on the role of ERRγ in endocrine and metabolic signaling.
    Regulation of ERRγ Gene Expression and Activity The functions of many NRs depend largely on their ligands. Interestingly, ERRγ is constitutively active due to the active conformation of its LBD, even in the absence of a ligand [20]. With regards to its regulation, recent reports have shown that ERRγ expression and activity are tightly controlled by different membrane receptors.
    Function of ERRγ Target Genes in Endocrine and Metabolic Pathways ERRγ is a key regulator of growth factors and hormones in various tissues (Table 1). It induces the angiogenic growth factors vascular endothelial growth factor (VEGF)-A and fibroblast growth factor (FGF)1 in muscle [7], and FGF21 in liver [15]. ERRγ positively regulates hepcidin, a key hormone synthesized and secreted by the liver that maintains iron homeostasis [25]. In vascular smooth muscle cells, ERRγ upregulates bone morphogenetic protein (BMP)2, a secreted ligand of the transforming growth factor (TGF)-β superfamily of proteins [52]. Additionally, ERRγ upregulates the synthesis of aromatase P450 (CYP19A1), a key enzyme involved in the synthesis of estrogen during trophoblast development in humans [27], and increases production of chorionic gonadotropin hormone that promotes syncytiotrophoblast differentiation 11, 53. It also stimulates 69 9 receptor production, by enhancing adrenal aldosterone synthase enzyme (Cyp11b2) expression [54]. These findings highlight the importance of ERRγ in endocrine signaling. ERRγ has been linked to the regulation of several key enzymes involved in nutrient metabolism, as it induces the gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) [13]. It also positively regulates the expression of pyruvate dehydrogenase kinase isozyme 4 (PDK4), a key regulator of pyruvate oxidation 26, 55. The coactivator PGC-1α stimulates the ability of ERRγ to induce PEPCK, G6Pase, and PDK4 expression [13], possibly involving the feed-forward mechanism described earlier. One of the most important and well-described roles of ERRγ is its active involvement in mitochondrial bioenergetics pathways, TCA cycle, fatty acid oxidation, OxPhos, and electron transport chain (ETC). During β-cell maturation, ERRγ upregulates several mitochondrial genes, such as Mdh1, Cox6a2, Atp2a2, Ndufs2, and Atp6v0a2, in pancreatic islets [31]. In the cardiac muscle, ERRγ upregulates several genes involved in fatty acid oxidation, including fatty acid-binding protein 3 (Fabp3), mitochondrial creatine kinase (Ckmt2), cytochrome c (Cycs), and ATP/ADP translocator (Slc25a4/ANT1); all crucial for the normal function of the heart 6, 56. In addition to glucose and energy metabolism, ERRγ is also involved in lipid and alcohol metabolism. In the liver, ERRγ induces LIPIN1 expression, leading to the formation of diacylglycerol (DAG); a direct precursor of triglycerides and phospholipids [12]. ERRγ also stimulates bile acid synthesis in the liver. CB1-induced ERRγ expression increases the expression of cholesterol 7α-hydroxylase (CYP7A1) which is the rate-limiting enzyme in the classical pathway of bile acid synthesis [14]. ERRγ increases the expression of cytochrome P450 2E1 (CYP2E1) as well; a key enzyme involved in the production of reactive oxygen species (ROS) in the liver 24, 57. ERRγ transcriptionally regulates several miRs. It induces gene expression of miR-127, which is known to downregulate the proto-oncogene BCL6 58, 59. Moreover, ERRγ also regulates miR subnetworks in the skeletal muscle. For example, it directly activates transcription of miR-208b and miR-499 that are involved in fiber type formation (discussed below) [10]. Interestingly, miRs have also been linked to the regulation of ERRγ. In breast cancer cells, miR-378* inhibits the expression of ERRγ, resulting in a metabolic switch from an oxidative to a glycolytic bioenergetics pathway and concomitant cell proliferation [60]. Similar to miRs, transcription factors are also regulated by ERRγ. ERRγ induces GATA4 transcription factor, which leads to induction of atrial natriuretic peptide in cardiomyocytes [29]. In response to ER-stress, ERRγ also upregulates the expression of the ER-bound transmembrane transcription factors ATF6α and cAMP-responsive element-binding protein 3-like protein 3 (CREBH) in hepatocytes 28, 61, indicating that ERRγ acts as a cell signal amplifier of ER stress that affects diverse physiological processes.