Retinoic acids induce neurosteroid biosynthesis in human glial GI-1 cells via the induction of steroidogenic genes

The steroids synthesized in the central nervous system (CNS) are the neurosteroids. Since little information is currently available concerning the roles of the retinoic acids (RAs) during steroidogenesis in the CNS, we investigated the effects of RAs upon their synthesis in our current study. Specifically, we analyzed the effects of all-trans-retinoic acid (ATRA) upon the expression of neurosteroid biosynthesis genes in the human glial cell line GI-1, in which the major steroidogenic genes are expressed. Treatment with ATRA (10 μM) induced a 4.9-fold increase in the expression of the cytochrome P450scc (CYP11A1) gene, the product of which cleaves the cholesterol side chain, a rate-limiting step during steroidogenesis. ATRA also strongly induced the expression of steroidogenic acute regulatory protein (StAR) and 3β-hydroxysteroid dehydrogenase (3β-HSD) (an increase of 5- and 50-fold, respectively). A retinoic acid receptor (RAR)-specific agonist, TTNPB, was unable to mimic this induction whereas a retinoid X receptor (RXR)-specific agonist, methoprene acid, in addition to 9-cis-RA, could do so. These data indicate that ATRA is isomerized to 9-cis-RA in the culture medium, as reported previously, and that 9-cis-RA activates the RXR. In addition, ATRA also induced the de novo synthesis of neurosteroids such as pregnenolone and progesterone. These results suggest that ATRA might induce the de novo neurosteroid synthesis via the induction of steroidogenic genes in human glial cells. The multiple effects of vitamin A upon CNS functions might therefore be partly explained by the induction of neurosteroidogenesis by RAs, since neurosteroids have also been reported to have multiple effects in the CNS.