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Division of Medical Sciences, Endocrinology, Institute of Biomedical Research, Medical School, University of Birmingham, Birmingham, B15 2TT, UK
1 Endocrine Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK
2 Paediatrics, University of Texas Southwestern Medical Center, Harry Hines Boulevard, Dallas, TX, USA
(Requests for offprints should be addressed to P M Stewart; Email: p.m.stewart{at}bham.ac.uk)
* (N Draper and Z Michailidou contributed equally to this work)
Two isozymes of 11ß-hydroxysteroid dehydrogenase (11ß-HSD) interconvert active cortisol and inactive cortisone. 11ß-HSD2 (renal) acts only as a dehydrogenase, converting cortisol to cortisone. 11ß-HSD1 (liver) is a bi-directional enzyme in cell homogenates, whereas in intact cells it typically displays oxo-reductase activity, generating cortisol from cortisone. We recently established that cortisone reductase deficiency is a digenic disease requiring mutations in both the gene encoding 11ß-HSD1 and in the gene for a novel enzyme located within the lumen of the endoplasmic reticulum (ER), hexose-6-phosphate dehydrogenase (H6PDH). This latter enzyme generates NADPH, the co-factor required for oxo-reductase activity. Therefore, we hypothesized that H6PDH expression may be an important determinant of 11ß-HSD1 oxo-reductase activity. Transient transfection of chinese hamster ovary (CHO) cells with 11ß-HSD1 resulted in the appearance of both oxo-reductase and dehydrogenase activities in intact cells. Co-transfection of 11ß-HSD1 with H6PDH increased oxo-reductase activity whilst virtually eliminating dehydrogenase activity. In contrast, H6PDH had no effect on reaction direction of 11ß-HSD2, nor did the cytosolic enzyme, glucose-6-phosphate dehydrogenase (G6PD) affect 11ß-HSD1 oxo-reductase activity. Conversely in HEK 293 cells stably transfected with 11ß-HSD1 cDNA, transfection of an H6PDH siRNA reduced 11ß-HSD1 oxo-reductase activity whilst simultaneously increasing 11ß-HSD1 dehydrogenase activity. In human omental preadipocytes obtained from 15 females of variable body mass index (BMI), H6PDH mRNA levels positively correlated with 11ß-HSD1 oxo-reductase activity, independent of 11ß-HSD1 mRNA levels. H6PDH expression increased 5.3-fold across adipocyte differentiation (P<0.05) and was associated with a switch from 11ß-HSD1 dehydrogenase to oxo-reductase activity. In conclusion, H6PDH is a crucial determinant of 11ß-HSD1 oxo-reductase activity in intact cells. Through its interaction with 11ß-HSD1, H6PDH may represent a novel target in the pathogenesis and treatment of obesity.
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