Sphingosine-1-phosphate rapidly increases cortisol biosynthesis and the expression of genes involved in cholesterol uptake and transport in H295R adrenocortical cells.

In the acute phase of adrenocortical steroidogenesis, adrenocorticotrophin (ACTH) activates a cAMP/PKA-signaling pathway that promotes the transport of free cholesterol to the inner mitochondrial membrane. We have previously shown that ACTH rapidly stimulates the metabolism of sphingolipids and the secretion of sphingosine-1-phosphate (S1P) in H295R cells. In this study, we examined the effect of S1P on genes involved in the acute phase of steroidogenesis. We show that S1P increases the expression of steroidogenic acute regulatory protein (StAR), 18-kDa translocator protein (TSPO), low-density lipoprotein receptor (LDLR), and scavenger receptor class B type I (SR-BI). S1P-induced StAR mRNA expression requires Gα(i) signaling, phospholipase C (PLC), Ca(2+)/calmodulin-dependent kinase II (CamKII), and ERK1/2 activation. S1P also increases intracellular Ca(2+), the phosphorylation of hormone sensitive lipase (HSL) at Ser(563), and cortisol secretion. Collectively, these findings identify multiple roles for S1P in the regulation of glucocorticoid biosynthesis.