Acknowledgments br Introduction Steroidogenesis the process
Introduction Steroidogenesis, the process of testosterone synthesis, occurs in the adrenal cortex, testis and ovary, and it is controlled by luteinizing hormone (LH), which is synthesized and secreted from the pituitary (Hanukoglu, 1992, Payne and Youngblood, 1995). In the testis, the stimulation of LH from the pituitary increases intracellular cAMP levels in Leydig cells and then results in steroidogenesis by increasing the expression of several steroidogenic genes (Payne and Youngblood, 1995, Habert et al., 2001, Odell et al., 1974). The first step of steroidogenesis is uptake of cholesterols into the inner mitochondrial membrane by steroidogenic acute regulatory protein (StAR) (Payne and Youngblood, 1995). Cholesterol within mitochondria is converted to pregnenolone by the cytochrome P450 side chain cleavage complex (P450scc), and pregnenolone is then transported to smooth endoplasmic reticulum (SER) and converted to testosterone through a series of steroidogenic enzymes, including 3β-hydroxysteroid dehydrogenase (3β-HSD) (Rasmussen et al., 2013) and cytochrome P450 17α-hydroxylase (P450c17) (Payne and Youngblood, 1995). Synthesized testosterone plays important roles in male sexual differentiation, reproductive development, and spermatogenesis initiation and maintenance. Nur77 (also known as NR4A1, NGFI-B, TR3 and NAK-1), an orphan nuclear receptor, is widely expressed in tissues, such as testis, ovary, muscle, thymus, adrenal gland, and Liproxstatin-1 receptor (Giguere, 1999, Law et al., 1992). As an immediate early response gene, Nur77 is induced by various stimuli, including fatty acids, stress, prostaglandins, growth factors, calcium, inflammatory cytokines, peptide hormones, and neurotransmitters (Maxwell and Muscat, 2006). Moreover, previous studies have demonstrated that LH, the regulator of testicular steroidogenesis, also induces Nur77 gene expression in Leydig cells (Song et al., 2001), which in turn regulates the expression of steroidogenic genes, such as StAR (Martin et al., 2008), P450c17 (Zhang and Mellon, 1997), and 3β-HSD type 2 (3β-HSD2) (Martin and Tremblay, 2005), through the Nur77-binding region within the promoter of these genes. Therefore, Nur77 in Leydig cells acts as one of major transcription factors involved in the regulation of steroidogenic genes. Several cytokines, including TNF-α (Hong et al., 2004) and TGF-β1 (Park et al., 2014a, Park et al., 2014b), as well as hormones, including estrogen (Lee et al., 2012) and thyroid hormone (Park et al., 2014a, Park et al., 2014b), in Leydig cells regulate LH/cAMP-activated steroidogenesis through the regulation of Nur77 transactivation. Estrogen receptor-related receptors (ERRs; ERRα, ERRβ and ERRγ) are also orphan nuclear receptors and are named after the sequence homology with estrogen receptors (ER), but their roles are distinctive from ERs (Giguere et al., 1988). ERRs are constitutively activated without binding to natural ligands (Xie et al., 2009), but this constitutive activity can be abolished by their inverse agonists such as GSK5182 (Kim et al., 2016, Joo et al., 2015, Tzameli and Moore, 2001). ERRs bind to DNA as monomers, which recognize estrogen receptor-related receptor response elements (ERREs) with the extended half-site consensus of TnAAGGTCA (Sladek et al., 1997, Johnston et al., 1997, Yang et al., 1996). ERRs also bind to estrogen-response elements (EREs) containing the recognition motif of AGGTCA as monomers, homodimers or heterodimers (Pettersson et al., 1996, Lu et al., 2001). Among ERRs, ERRγ is expressed in various tissues, such as brain, heart, muscle and liver, and it plays roles in energy homeostasis, diabetes and cancers (Huss et al., 2015). However, the expression and role of ERRγ in reproductive organs are yet not fully defined.
Materials and methods
Discussion Testicular steroidogenesis in Leydig cells is regulated by multiple signaling pathways and transcription factors that generate both positive and negative effects on steroidogenic response. LH/cAMP stimulation is a major regulatory pathway of testicular steroidogenesis, which rapidly induces the expression of Nur77, and in turn upregulates the expression of steroidogenic genes. In this study, we demonstrated that ERRγ is expressed in mouse Leydig cells and increases the synthesis of testicular testosterone. Recently, the expression of ERRγ in primary and tumor Leydig cells was reported although its role in Leydig cells was not addressed (Pardyak et al., 2016).