Oral Presentation The International Congress of Neuroendocrinology 2014

Dynamics of adrenal glucocorticoid steroidogenesis in health and disease (#84)

Francesca Spiga 1 , Zidong Zhao 1 , Jamie J Walker 1 , Ben Gibbison 1 , Stafford L Lightman 1
  1. University of Bristol, Bristol, Bristol and Bath, Somerset, United Kingdom

We have recently shown that the ultradian rhythm of glucocorticoid secretion depends on pulsatile ACTH in the plasma and this is associated with the pulsatile expression of steroidogenic genes in the rat adrenal gland. In this study we characterised the molecular pathway regulating rapid glucocorticoid synthesis in the zona fasciculata of the adrenal gland in the rat. We used RTqPCR and Western immune blotting to investigate transcriptional activation, and synthesis and activity of proteins involved in steroidogenesis in rats exposed to either an ultradian pulse of ACTH, or to an immune stress (LPS). We found that ultradian corticosterone secretion in the rat depends primarily on non-genomic events, including phosphorylation of proteins involved in cholesterol metabolism. In contrast, glucocorticoid synthesis in response to LPS is also regulated by changes in steroidogenic protein levels, including StAR and its transcriptional regulator DAX1. Our results have important clinical implications. Indeed, we have recently shown that patients undergoing cardiac surgery have an increased adrenal sensitivity to ACTH, with elevated cortisol levels despite normal ACTH levels during the 24h period after surgery. We have investigated the mechanism underlying these changes in adrenal sensitivity and have found that, consistent with human, rats exposed to LPS also have an increased adrenal responsiveness to ACTH, and that this effect is paralleled by changes both in steroidogenic proteins and in proteins involved in ACTH signalling.
Our data show that the ultradian rhythm of glucocorticoids is regulated by rapid dynamic changes in the adrenal steroidogenic pathway and that disruption of these dynamics can lead to dysfunctional HPA axis activity.