Regulation of metabolic pathways in steroidogenic cells by Ad4BP/SF-1

Ad4BP/SF-1 (NR5A1), a member of the nuclear receptor superfamily, is known to play crucial roles in the regulation of steroidogenesis in the gonads and adrenal cortex, and many studies have demonstrated that all steroidogenic genes are direct targets of Ad4BP/SF-1. In addition, in vivo KO studies demonstrated that no steroidogenic organs formed in gene-disrupted mice, strongly suggesting that Ad4BP/SF-1 is essential for the development of the gonads and adrenal gland. However, it remains unclear how Ad4BP/SF-1 regulates the development of the steroidogenic organs and which additional non-steroidogenic genes are targeted. We surveyed the target genes of Ad4BP/SF-1 in steroidogenic cells by mRNA deep sequencing and ChIP-sequence analyses using an Ad4BP/SF-1 antibody. Nearly all genes in energy-producing glycolytic pathways were found to be regulated by Ad4BP/SF-1. We also showed that the key genes implicated in NADPH production are the direct targets. Since sufficient supplies of ATP and NADPH are necessary for cellular survival and production of steroids, Ad4BP/SF-1 possibly orchestrates tissue-specific steroidogenic pathway and these housekeeping metabolic pathways.