Mutations in the genes encoding 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency

Abstract

In cortisone reductase deficiency (CRD), activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS; refs. 1,2). This suggests a defect in the gene HSD11B1 encoding 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), a primary regulator of tissue-specific glucocorticoid bioavailability. We identified intronic mutations in HSD11B1 that resulted in reduced gene transcription in three individuals with CRD. In vivo, 11beta-HSD1 catalyzes the reduction of cortisone to cortisol whereas purified enzyme acts as a dehydrogenase converting cortisol to cortisone. Oxo-reductase activity can be regained using a NADPH-regeneration system and the cytosolic enzyme glucose-6-phosphate dehydrogenase. But the catalytic domain of 11beta-HSD1 faces into the lumen of the endoplasmic reticulum (ER; ref. 6). We hypothesized that endolumenal hexose-6-phosphate dehydrogenase (H6PDH) regenerates NADPH in the ER, thereby influencing directionality of 11beta-HSD1 activity. Mutations in exon 5 of H6PD in individuals with CRD attenuated or abolished H6PDH activity. These individuals have mutations in both HSD11B1 and H6PD in a triallelic digenic model of inheritance, resulting in low 11beta-HSD1 expression and ER NADPH generation with loss of 11beta-HSD1 oxo-reductase activity. CRD defines a new ER-specific redox potential and establishes H6PDH as a potential factor in the pathogenesis of PCOS.

Increased In Vivo Regeneration of Cortisol in Adipose Tissue in Human Obesity and Effects of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Carbenoxolone

“…This rapid time course suggests that there may be altered kinetics of the enzyme over and above changes in protein levels. One mechanism might involve hexose-6-phosphate dehydrogenase, an enzyme co-localized with 11HSD1 in the lumen of the endoplasmic reticulum that may modulate the supply of NADPH cofactor for cortisone reduction (41)(42)(43). Further dissection of the mechanisms of acute regulation of 11HSD1 activity by insulin in adipose tissue may be particularly valuable, as the current data suggest that obese men resist this effect.…”

Rapid mechanisms of glucocorticoid signaling in the Leydig cell☆

“…H6PDH uses NADP+ as a co-factor and glucose-6-phosphate (G6P) as a substrate. It is well established that pyridine nucleotides are impermeable to SER membrane and that G6P can be transported into SER lumen by G6P transporting protein [55][56][57][58]. This generates NADPH from NADP+ increasing NADPH/NADP+ ratio which drives 11βHSD1 to function enzymatically as a reductase.…”

Extra-adrenal regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1: physiological regulator and pharmacological target for energy partitioning

“…The molecular basis for the disorder is also complex. It appears most likely that inactivating mutations in hexose-6-phosphate dehydrogenase (Draper et al 2003), an enzyme closely associated with 11b-HSD1 in the lumen of the endoplasmic reticulum, result in an inadequate supply of NADPH cofactor for 11b-HSD1 reductase activity. In hexose-6-phosphate dehydrogenase-deficient mice this situation results in a 'switch' of 11b-HSD1 to the dehydrogenase direction (Lavery et al 2006).…”