Transcriptional coactivator with PDZ‐binding motif (TAZ) plays crucial role in maintaining testicular structure and function via regulation of senescence of spermatogenic cells. However, it remains unclear whether TAZ is involved in testosterone biosynthesis in testicular Leydig cells. We found that TAZ deficiency caused aberrant Leydig cell expansion and increased lipid droplet formation, which was significantly associated with increased lipogenic enzyme expression. Additionally, the expression of key steroidogenic enzymes, including steroidogenic acute regulatory protein, cytochrome P450 (CYP) 11A1, CYP17A1, and 3β‐hydroxysteroid dehydrogenase, was greatly increased in TAZ‐deficient testes and primary Leydig cells. Interestingly, the transcriptional activity of nuclear receptor 4 A1 (NR4A1) was dramatically suppressed by TAZ; however, the protein expression and the subcellular localization of NR4A1 were not affected by TAZ. TAZ directly associated with the N‐terminal region of NR4A1 and substantially suppressed its DNA‐binding and transcriptional activities. Stable expression of TAZ in the mouse Leydig TM3 cell line decreased the expression of key steroidogenic enzymes, whereas knockdown of endogenous TAZ in TM3 cells increased transcripts of steroidogenic genes induced by NR4A1. Consistently, testosterone production was enhanced within TAZ‐deficient Leydig cells. However, TAZ deficiency resulted in decreased testosterone secretion caused by dysfunctional mitochondria and lysosomes. Therefore, TAZ plays essential role in NR4A1‐induced steroidogenic enzyme expression and testosterone production in Leydig cells.
Testosterone is a hormone essential for male reproductive function. It is produced primarily by Leydig cells in the testicle through activation of steroidogenic acute regulatory protein and a series of steroidogenic enzymes, including a cytochrome P450 side-chain cleavage enzyme (cytochome P450 family 11 subfamily A member 1), 17α-hydroxylase (cytochrome P450 family 17 subfamily A member 1), and 3β-hydroxysteroid dehydrogenase. These steroidogenic enzymes are mainly regulated at the transcriptional level, and their expression is increased by the nuclear receptor 4A1. However, the effect on Leydig cell function of a small molecule-activating ligand, amodiaquine (AQ), is unknown. We found that AQ effectively and significantly increased testosterone production in TM3 and primary Leydig cells through enhanced expression of steroidogenic acute regulatory protein, cytochome P450 family 11 subfamily A member 1, cytochrome P450 family 17 subfamily A member 1, and 3β-hydroxysteroid dehydrogenase. Concurrently, AQ dose-dependently increased the expression of 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in the cholesterol synthesis pathway, through induction of the transcriptional and DNA-binding activities of nuclear receptor 4A1, contributing to increased cholesterol synthesis in Leydig cells. Furthermore, AQ increased the expression of fatty acid synthase and diacylglycerol acyltransferase and potentiated de novo synthesis of fatty acids and triglycerides (TGs). Lipidomics profiling further confirmed a significant elevation of intracellular lipid and TG levels by AQ in Leydig cells. These results demonstrated that AQ effectively promotes testosterone production and de novo synthesis of cholesterol and TG in Leydig cells, indicating that AQ may be beneficial for treating patients with Leydig cell dysfunction and subsequent testosterone deficiency.
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