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Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11β-hydroxysteroid dehydrogenase type 1
Open accessAbstract
Two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) interconvert active cortisol and inactive cortisone. 11β-HSD2 (renal) acts only as a dehydrogenase, converting cortisol to cortisone. 11β-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 11β-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 11β-HSD1 oxo-reductase activity. Transient transfection of chinese hamster ovary (CHO) cells with 11β-HSD1 resulted in the appearance of both oxo-reductase and dehydrogenase activities in intact cells. Co-transfection of 11β-HSD1 with H6PDH increased oxo-reductase activity whilst virtually eliminating dehydrogenase activity. In contrast, H6PDH had no effect on reaction direction of 11β-HSD2, nor did the cytosolic enzyme, glucose-6-phosphate dehydrogenase (G6PD) affect 11β-HSD1 oxo-reductase activity. Conversely in HEK 293 cells stably transfected with 11β-HSD1 cDNA, transfection of an H6PDH siRNA reduced 11β-HSD1 oxo-reductase activity whilst simultaneously increasing 11β-HSD1 dehydrogenase activity. In human omental preadipocytes obtained from 15 females of variable body mass index (BMI), H6PDH mRNA levels positively correlated with 11β-HSD1 oxo-reductase activity, independent of 11β-HSD1 mRNA levels. H6PDH expression increased 5.3-fold across adipocyte differentiation (P<0.05) and was associated with a switch from 11β-HSD1 dehydrogenase to oxo-reductase activity. In conclusion, H6PDH is a crucial determinant of 11β-HSD1 oxo-reductase activity in intact cells. Through its interaction with 11β-HSD1, H6PDH may represent a novel target in the pathogenesis and treatment of obesity.
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“as colocalized hexose-6-phosphate dehydrogenase (H6PDH) regenerates NADPH required for its cortisone reductase activity”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [109]
In the citing paper
“HSD11B1 is a bidirectional enzyme, but primarily catalyzes the reduction of 11-ketosteroids in vivo”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [109]
In the citing paper
“mainly activating cortisone to cortisol [109]”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [109]
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Self-citationTissue-Specific Dysregulation of Cortisol Metabolism in Human Obesity
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The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders
Miller, W. L., & Auchus, R. J. (2011) · Endocrine Reviews · doi:10.1210/er.2010-0013 · Cited by 2,458
11β-hydroxysteroid dehydrogenases: Intracellular gate-keepers of tissue glucocorticoid action
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Metadata
- Authors
- Bujalska, I. J., Draper, N., Michailidou, Z., Tomlinson, J. W., White, P. C., Chapman, K. E., Walker, E. A., & Stewart, P. M.
- Affiliations
- University of Birmingham (GB)
- Western General Hospital (GB)
- The University of Texas Southwestern Medical Center (US)
- Venue
- Journal of Molecular Endocrinology
- Publisher
- Bioscientifica
- Published
- 2005-06-01
- Volume
- 34
- Issue
- 3
- Pages
- 675-684
- ISSN
- 0952-5041 (ISSN-L)
- 1479-6813
- OpenAlex
- W2145137221
- Semantic Scholar
- ea6c19382d7728e2ab3b59c90109625c30738483
- Cited by
- 165
- References
- 65
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 4 · 2015: 7 · 2014: 10 · 2013: 10 · 2012: 6
- FWCI
- 13.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Imperial College London
- Medical Research Council
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
- Keywords
- hexose-6-phosphate dehydrogenase, NADPH, endoplasmic reticulum, cortisol metabolism, cortisone, glucose-6-phosphate dehydrogenase, adipogenesis, preadipocytes, siRNA knockdown, isozymes, body mass index
- MeSH terms
- Adult, Animals, Base Sequence, Carbohydrate Dehydrogenases, Female, Cricetinae, Humans, RNA, Messenger, Blotting, Western, Polymerase Chain Reaction, CHO Cells, DNA Primers, RNA, Small Interfering, 11-beta-Hydroxysteroid Dehydrogenase Type 1
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