CREBZF/c-Jun complex regulates ApoE expression, reducing cholesterol and influencing female steroidogenesis.

Ovarian secretion of steroid hormones is fundamental for female reproductive health, governing processes like the estrous cycle and follicular development. Dysregulation in steroidogenesis can lead to significant reproductive issues. While transcription factors are known to regulate gene expression in these pathways, the specific role of CREBZF, a basic leucine zipper transcription factor, in female reproduction and steroid hormone synthesis has been largely unexplored. Understanding its involvement could reveal novel regulatory mechanisms and potential therapeutic targets for reproductive disorders.

Researchers investigated CREBZF's role using whole ovarian knockout of CREBZF in female mice, observing effects on the estrous cycle and hormone levels. They also generated Cyp17a1-positive cell conditional knockout mice to assess specific impacts on serum testosterone, maternal behavior, and offspring survival. In vitro, CREBZF was knocked down in NCI-H295R cells induced for steroidogenesis. RNA sequencing (RNA-seq) was performed on CREBZF-knockdown NCI-H295R cells to identify differentially expressed genes. Further experiments included co-immunoprecipitation and chromatin immunoprecipitation (ChIP) to confirm protein interactions and DNA binding, alongside luciferase reporter assays to characterize transcriptional regulation.

Whole ovarian knockout of CREBZF in female mice significantly affected the estrous cycle, antral follicle development, and altered testosterone and estradiol levels. Conditional knockout of CREBZF in Cyp17a1-positive cells resulted in altered serum testosterone during estrus, impaired postpartum maternal behavior, and significantly reduced offspring survival, associated with abnormal corticosterone and oxytocin levels. In NCI-H295R cells, CREBZF knockdown reduced testosterone and corticosterone secretion. RNA sequencing revealed 51 differentially expressed genes enriched in steroidogenesis-related pathways. Importantly, CREBZF knockdown also reduced c-Jun and ApoE expression, leading to a significant decrease in intracellular cholesterol. > The CREBZF/c-Jun complex directly regulates ApoE expression by binding to its promoter, with CREBZF enhancing c-Jun-mediated activation of ApoE at Site1 (-299 to -286 bp) but inhibiting it at Site2 (+70 to +83 bp), demonstrating a complex, site-specific regulatory mechanism.