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J. Biol. Chem., Vol. 282, Issue 37, 27030-27036, September 14, 2007

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11-Hydroxysteroid Dehydrogenase Type 1 Regulation by Intracellular Glucose 6-Phosphate Provides Evidence for a Novel Link between Glucose Metabolism and Hypothalamo-Pituitary-Adrenal Axis Function^*

Elizabeth A. Walker¹, Adeeba Ahmed¹², Gareth G. Lavery, Jeremy W. Tomlinson³, So Youn Kim, Mark S. Cooper, Jonathan P. Ride^¶, Beverly A. Hughes, Cedric H. L. Shackleton, Patrick McKiernan^||, Elwyn Elias^**, Janice Y. Chou, and Paul M. Stewart⁴

From the Endocrinology, Division of Medical Sciences and ^¶Biological Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TH, United Kingdom, the NICHD, National Institutes of Health, Bethesda, Maryland, 20892, the ^||Liver Unit, Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom, and the ^**Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Edgbaston, Birmingham, B15 2TH, United Kingdom

Microsomal glucose-6-phosphatase- (G6Pase-) and glucose 6-phosphate transporter (G6PT) work together to increase blood glucose concentrations by performing the terminal step in both glycogenolysis and gluconeogenesis. Deficiency of the G6PT in liver gives rise to glycogen storage disease type 1b (GSD1b), whereas deficiency of G6Pase- leads to GSD1a. G6Pase- shares its substrate (glucose 6-phosphate; G6P) with hexose-6-phosphate-dehydrogenase (H6PDH), a microsomal enzyme that regenerates NADPH within the endoplasmic reticulum lumen, thereby conferring reductase activity upon 11-hydroxysteroid dehydrogenase type 1 (11-HSD1). 11-HSD1 interconverts hormonally active C11-hydroxy steroids (cortisol in humans and corticosterone in rodents) to inactive C11-oxo steroids (cortisone and 11-dehydrocorticosterone, respectively). In vivo reductase activity predominates, generating active glucocorticoid. We hypothesized that substrate (G6P) availability to H6PDH in patients with GSD1b and GSD1a will decrease or increase 11-HSD1 reductase activity, respectively. We investigated 11-HSD1 activity in GSD1b and GSD1a mice and in two patients with GSD1b and five patients diagnosed with GSD1a. We confirmed our hypothesis by assessing 11-HSD1 in vivo and in vitro, revealing a significant decrease in reductase activity in GSD1b animals and patients, whereas GSD1a patients showed a marked increase in activity. The cellular trafficking of G6P therefore directly regulates 11-HSD1 reductase activity and provides a novel link between glucose metabolism and function of the hypothalamo-pituitary-adrenal axis.

Received for publication, May 21, 2007 , and in revised form, May 11, 2007.

^* This work was supported by Programme grant support (Ref. 066357) and Project grant support (Ref. 074088) from the Wellcome Trust (to E. A. W. and P. M. S.) and by National Institutes of Health support Grant 1Z01HD000912-27 (to J. Y. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to the work.

² A Wellcome Trust Medical Research Council Clinical Training Fellow (Ref. G84/6638).

³ A Wellcome Trust Clinician Scientist Fellow (Ref. 075322).

⁴ To whom correspondence should be addressed. Tel.: 44-121-4158708; Fax: 44-121-4158708; E-mail: p.m.stewart{at}bham.ac.uk.

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