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J. Biol. Chem., Vol. 281, Issue 10, 6546-6551, March 10, 2006

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Hexose-6-phosphate Dehydrogenase Knock-out Mice Lack 11-Hydroxysteroid Dehydrogenase Type 1-mediated Glucocorticoid Generation^*

Gareth G. Lavery, Elizabeth A. Walker¹, Nicole Draper^¶1, Pancharatnam Jeyasuria, Josep Marcos^||, Cedric H. L. Shackleton^||, Keith L. Parker, Perrin C. White^¶, and Paul M. Stewart²

From the Departments of Internal Medicine and ^¶Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Department of Medicine, Division of Medical Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TH, United Kingdom, and ^||Children's Hospital Oakland Research Institute, Oakland, California 94609

The local generation of active glucocorticoid by NADPH-dependent, 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) oxoreductase activity, has emerged as an important factor in regulating hepatic glucose output and visceral adiposity. We have proposed that this NADPH is generated within the endoplasmic reticulum by the enzyme hexose-6-phosphate dehydrogenase. To address this hypothesis, we generated mice with a targeted inactivation of the H6PD gene. These mice were unable to convert 11-dehydrocorticosterone (11-DHC) to corticosterone but demonstrated increased corticosterone to 11-DHC conversion consistent with lack of 11-HSD1 oxoreductase and a concomitant increase in dehydrogenase activity. This increased corticosterone clearance in the knock-out mice resulted in a reduction in circulating corticosterone levels. Our studies define the critical requirement of hexose-6-phosphate dehydrogenase for 11-HSD1 oxoreductase activity and add a new dimension to the investigation of 11-HSD1 as a therapeutic target in patients with the metabolic syndrome.

Received for publication, November 28, 2005 , and in revised form, December 15, 2005.

^* This study was supported by Grants 066357 (to P. M. S.) and 074088/Z/04/Z (to E. A. W. and P. M. S.) from the Wellcome Trust, Grant DK54480 from the National Institutes of Health (NIH) and the Wilson Center for Biomedical Research (to K. L. P.), and NIH Grant DK068101 (to P. C. W.). 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 These authors contributed equally to this work.

² To whom correspondence should be addressed: Division of Medical Sciences, University of Birmingham, Birmingham, B15 2TH, United Kingdom. Tel.: 44-121-415-87-08; Fax: 44-121-415-8712; E-mail: p.m.stewart{at}bham.ac.uk.

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