Endocrinol Metab.  2020 Dec;35(4):756-764. 10.3803/EnM.2020.402.

Coordination of Multiple Cellular Processes by NR5A1/Nr5a1

• Morohashi Ki
• Inoue M
• Baba T

• KMID: 2511002
• DOI: http://doi.org/10.3803/EnM.2020.402

Abstract

The agenesis of the gonads and adrenal gland in revealed by knockout mouse studies strongly suggested a crucial role for Nr5a1 (SF-1 or Ad4BP) in organ development. In relation to these striking phenotypes, NR5A1/Nr5a1 has the potential to reprogram cells to steroidogenic cells, endow pluripotency, and regulate cell proliferation. However, due to limited knowledge regarding NR5A1 target genes, the mechanism by which NR5A1/Nr5a1 regulates these fundamental processes has remained unknown. Recently, newlyestablished technologies have enabled the identification of NR5A1 target genes related to multiple metabolic processes, as well as the aforementioned biological processes. Considering that active cellular processes are expected to be accompanied by active metabolism, NR5A1 may act as a key factor for processes such as cell differentiation, proliferation, and survival by coordinating these processes with cellular metabolism. A complete and definite picture of the cellular processes coordinated by NR5A1/Nr5a1 could be depicted by accumulating evidence of the potential target genes through whole genome studies.

Keyword

NR5A1; Steroidogenic factor 1; Ad4BP; Knockout; Cell proliferation; Glycolysis; Gonads; Adrenal glands; Cell differentiation

Figure

• 

  Fig. 1 Genes implicated in steroid hormone synthetic pathways. Pathways for the synthesis of cortisol (glucocorticoids) and aldosterone (mineralocorticoids) in the adrenal cortex, and testosterone (androgen) and 17β-estradiol (estrogen) in the gonads from cholesterol are shown. Genes implicated in the pathways are indicated in the closed boxes.

• 

  Fig. 2 Effects of cell type-specific Nr5a1 disruption. Nr5a1 expression starts at the progenitor cell stage and reaches a plateau in matured fetal Leydig cells (FLCs) and Sertoli cells. (A) Nr5a1 was disrupted in FLCs or progenitor cells using the Cyp11a1-Cre or FLE-Cre mouse line, respectively. Thus, Nr5a1 expression (indicated by broad arrows) was expected to increase once and then be abolished in the FLCs or progenitor cells (broken arrows). (B) Nr5a1 was disrupted in Sertoli cells using the Amh-Cre mouse line. The expression was expected to increase once and then be abolished after the differentiation of Sertoli cells (indicated by a broad arrow and a broken arrow). The effects of Nr5a1 on the presence of the cell types and the cellular functions in the conditional knockout mice are summarized on the right side.

• 

  Fig. 3 Cellular metabolisms regulated by Nr5a1. Chromatin immunoprecipitation (ChIP)-seq studies revealed that NR5A1 regulates genes involved in glycolysis (shown by an orange arrow), cholesterogenesis (blue arrow), and steroidogenesis (blue arrow). In addition, NR5A1 regulates genes whose products mediate nicotinamide-adenine dinucleotide phosphate (NADPH) synthesis (orange arrow). Glycolysis and NADPH synthesis pathways produce the energized molecules adenosine triphosphate (ATP) and NADPH, respectively, whereas cholesterogenic and steroidogenic pathways consume these energized molecules. Because pyruvate, the product of glycolysis, can be converted to acetyl-coenzyme A (CoA), the starting material for cholesterogenesis, and cholesterol is used for steroidogenesis, Nr5a1 might thus be considered to coordinate multiple metabolic pathways to achieve efficient steroidogenesis.

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  Fig. 4 Possible coordination between cellular activities and metabolisms by Nr5a1. Genes involved in multiple metabolic pathways, such as glycolysis, cholesterogenesis, steroidogenesis, and nicotinamide-adenine dinucleotide phosphate (NADPH) synthesis, are regulated by Nr5a1. Nr5a1 potentially regulates the processes of cell proliferation, differentiation, and survival. Synthesis of DNA, RNA, proteins, and lipids are thought to accompany these cellular activities. The energized molecules, adenosine triphosphate (ATP) and/or NADPH, are required for the production of these cellular components. By supplying the energized molecules, Nr5a1 may coordinate cellular metabolisms and activities. CoA, coenzyme A.

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