The novel congenital adrenal hyperplasia variant, apparent cortisone reductase deficiency (ACRD), has highlighted the significance of subcellular redox potential in regulating glucocorticoid hormone action. In ACRD, there is an attenuation of perceived glucocorticoid (GC) concentrations which results in up-regulation of adrenal androgen production as a consequence of increased hypothalamic-pituitary-adrenal (HPA) activity. We have recently identified mutations in the enzyme hexose-6- phosphate dehydrogenase (H6PDH) that cause ACRD. H6PDH is a bi-functional enzyme that catalyses the first two reactions of an endoplasmic reticulum (ER) pentose phosphate pathway. The physiological substrate for H6PDH is glucose-6-phosphate (G6P), delivered to the ER via the G6P transporter. Metabolism of G6P via H6PDH generates a high local concentration of NADPH. We postulated that H6PDH provides NADPH to another ER enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which acts primarily in vivo as an oxo-reductase, converting intracellular inactive GC to active GC. Our recent generation of a H6PDH knockout mouse confirms that without provision of NADPH, 11β-HSD1 lacks oxo-reductase activity. These mice also display abnormalities in blood glucose homeostasis and HPA axis function. As such, mutant mice fail to gain weight appropriately on a regular or high fat diet, have fasting hypoglycaemia and improved glucose tolerance. Intriguingly, this model has a novel and progressive type II fibre vacuolar myopathy associated with abnormal glycogen storage that results in atrophy, weakness and a degeneration of body condition. The precise underlying biochemistry mediating this is currently under investigation.
ACRD is a fascinating human experiment of nature that highlights the contribution of redox potential regulation to pre-receptor regulation of steroid hormone action. The H6PDH knockout mouse is a valuable model offering insight not only into glucocorticoid metabolism and associated patho-physiology, but also new functions of H6PDH that are yet to be explored.