Transcription regulation of NRF1 on StAR reduces testosterone synthesis in hypoxemic murine.

Male chronic obstructive pulmonary disease (COPD) and sleep apnea patients are associated with serum testosterone level decline because of hypoxemia, resulting in male sexual dysfunction and lower reproductive capacity. Although testosterone replacement therapy used in clinic achieves good results, the side effects indicates that understanding the mechanism followed with targeted treatments are more meaningful. The known mechanism of Hypoxia-inducible factor-1 (HIF-1) mediated steroidogenic acute regulatory protein (StAR) repression did not well explain the reason of hypoxia induced testosterone decline. Our primary results indicated Nuclear respiratory factor 1(NRF1) might be participate in StAR transcription regulation. The study aims to identify the mechanism of the regulation of StAR by NRF1, providing an explanation for the decrease of testosterone induced by hypoxemia. Testosterone level and StAR were determined in COPD model rats, sleep apnea model mice and hypoxia rats (10%O2). Results indicated NRF1, StAR and testosterone decreased in testis and ovary and increased in adrenal. Regulation of NRF1 expression under normoxia or hypoxia induced synchronous changes of both StAR and testosterone, indicating the decrease of NRF1 induced StAR repression in hypoxemia were the main cause of serum testosterone decline. The results were confirmed by dual-luciferase reporter assays, regulation of NRF1 synchronously altered the transcriptional activity of StAR. By ChIP, EMSA supershift, NRF1 was found to bind to the Star promoter region. Mutation assays identified two NRF1-binding sites on mouse Star promoter. These findings indicated that NRF1 positivly regulated Star transcription through directly binding to the Star promoter at -1445/-1422 and -44/-19.