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Regulation of Glucocorticoid Production by Nuclear Lipid Metabolism

Glucocorticoids are produced in response to activation of a cAMP signaling cascade that increases the interaction of the nuclear receptor steroidogenic factor 1 (SF1) with the promoters of multiple target genes. We have previously identified phosphatidic acid (PA) and sphingosine (SPH) as an agonist and antagonist for SF1, respectively. Based on the nuclear localization of SF1, we hypothesized that cAMP signaling regulates the ability of SF1 to activate target genes by modulating the nuclear concentrations of PA and SPH. We show that cAMP rapidly activates nuclear phospholipid and sphingolipid metabolism, where PA production is catalyzed by diacylglycerol kinase theta (DGKQ) and SPH biosynthesis by acid ceramidase (ASAH1). Ligand binding is facilitated by the ability of these lipid metabolizing enzymes to bind directly to the receptor. Silencing ASAH1 increases the capacity of adrenocortical cells to secrete cortisol, primarily by increasing the expression of genes required for steroid hormone production. In contrast, suppression of DGKQ expression attenuates the ability of SF1 to activate target gene transcription and impairs hormone biosynthesis. Collectively, we show that ASAH1 and DGKQ are novel coregulatory proteins that regulate SF‐1 function by directly binding to the receptor on SF‐1‐target gene promoters and identify a key role for nuclear lipid metabolism in regulating gene transcription.