Estrogen receptor-related receptor γ regulates testicular steroidogenesis through direct and indirect regulation of steroidogenic gene expression

Biosynthesis of testosterone, which mainly occurs in testicular Leydig cells, is controlled by steroidogenic proteins, such as StAR and P450c17. Although estrogen-related receptor gamma (ERR gamma), an orphan nuclear receptor, is expressed in the testis, its role is not well understood. In this study, we investigated the expression of ERR gamma in Leydig cells and its molecular action on testicular steroidogenesis. ERR gamma is expressed in mouse Leydig cells from pre-pubertal stages. ERR gamma overexpression in primary Leydig cells elevated the production of testosterone with a marked increase of P450c17 expression at both mRNA and protein levels, albeit decreased expression of StAR. Promoter-reporter analyses showed that ERR gamma directly regulated the P450c17 promoter. Further deletion mutant analyses of the P450c17 promoter revealed that ERR gamma activated expression of the P450c17 gene by binding to an ERR gamma response element within the P450c17 promoter. Meanwhile, ERR gamma suppressed cAMP-induced activation of the StAR promoter, which was likely due to ERR gamma-mediated inhibition of the transcriptional activity of Nur77, which is induced by cAMP and regulates StAR gene expression in Leydig cells. Interestingly, ERR gamma coexpression also decreased the protein level of Nur77, which occurred through proteasomal degradation, suggesting ERR gamma-mediated regulation of steroidogenesis at another level. Taken together, these findings suggest that ERR gamma regulates testicular steroidogenesis, both directly controlling and indirectly fine-tuning the expression of steroidogenic genes. (C) 2017 Elsevier B.V. All rights reserved.