5 years ago

Role of CYP51 in the regulation of T3 and FSH-induced steroidogenesis in female mice.

Cytochrome P450 lanosterol 14α-demethylase (CYP51) is a key enzyme in sterols and steroids biosynthesis that involved in folliculogenesis and oocyte maturation, which is regulated by follicle stimulating hormone (FSH), as a key reproductive hormone during follicular development. Thyroid hormone (TH) is also important for normal reproductive function. Although T3 enhances FSH-induced preantral follicle growth, whether and how TH combines with FSH to regulate CYP51 expression during preantral to early antral transition stage is unclear. The objective of this study was to determine the cellular and molecular mechanisms by which T3 and FSH regulate CYP51 expression and steroid biosynthesis during preantral follicle growth. Our results indicated that CYP51 expression was upregulated in granulosa cells by FSH, and this response was enhanced by T3. Moreover, knockdown CYP51 also decreased cell viability. Meanwhile, gene knockdown also blocked T3 and FSH-induced estradiol (E2) and progesterone (P4) synthesis. These changes were accompanied by up-regulation of phosphor-GATA-4 content. Results of siRNA analysis showed that knockdown of GATA-4 significantly declined CYP51 gene expression as well as E2/P4 levels. Furthermore, TRβ was necessary to the activation of PI3K/Akt, which was required to the regulation of CYP51 expression and activated GATA-4 was also involved these processes. Our data demonstrate that T3 and FSH co-treatment potentiates cellular development and steroid biosynthesis via CYP51 upregulation, which are mediated through the activation of the PI3K/Akt pathway. Meanwhile, activated GATA-4 is also involved in this regulatory system. These findings suggest that CYP51 is a novel mediator of T3 and FSH-induced follicular development.

Publisher URL: http://doi.org/10.1210/en.2017-00249

DOI: 10.1210/en.2017-00249

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