Cited by 165Adrenal Hormones and DisordersHormonal Regulation and HypertensionSexual Differentiation and Disorders

Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11β-hydroxysteroid dehydrogenase type 1

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Bujalska, Iwona J, Draper, Nicole, Michailidou, Zoi, Tomlinson, Jeremy W, White, Perrin C, Chapman, Karen E, Walker, Elizabeth A, Stewart, Paul M·2005·Journal of Molecular Endocrinology

Abstract

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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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
Published
2005-06-01
Volume
34
Issue
3
Pages
675-684
ISSN
  • 0952-5041 (ISSN-L)
  • 1479-6813
OpenAlex
W2145137221
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
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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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