CREBZF/c-Jun modulates ApoE-mediated cholesterol transport to influence female steroid hormone synthesis

Ovarian secretion of steroid hormones is crucial for female reproductive health. CREBZF, a basic leucine zipper transcription factor, can heterodimerize with other transcription factors to regulate genes involved in various biological processes. This study investigates the role of CREBZF in female reproduction and steroid hormone synthesis regulation. Whole ovarian knockout of CREBZF affects the estrous cycle, antral follicle development, and testosterone and estradiol levels in female mice. Conditional knockout of CREBZF in Cyp17a1-positive cells results 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 induced for steroidogenesis, CREBZF knockdown reduced testosterone and corticosterone secretion. RNA sequencing of CREBZF-knockdown NCI-H295R cells identified 51 differentially expressed genes enriched in steroidogenesis-related pathways. CREBZF knockdown also reduced c-Jun and ApoE expression, with a significant decrease in intracellular cholesterol. CREBZF interacts with c-Jun and binds to the ApoE promoter to regulate expression. Database screening identified two CREBZF/c-Jun binding sites, where CREBZF enhances c-Jun-mediated activation of ApoE at Site1 ( -299 to -286 bp), but inhibits it at Site2 (+70 to +83 bp). In conclusion, the CREBZF/c-Jun complex regulates ApoE expression, influencing cholesterol levels and female steroidogenesis, which is crucial for reproductive function.