Hexose-6-phosphate dehydrogenase knock-out mice lack 11β- hydroxysteroid dehydrogenase type 1-mediated glucocorticoid generation

Gareth G. Lavery, Elizabeth A. Walker, Nicole Draper, Pancharatnam Jeyasuria, Josep Marcos, Cedric H L Shackleton, Keith L. Parker, Perrin C. White, Paul M. Stewart

Research output: Contribution to journalArticlepeer-review

161 Scopus citations

Abstract

The local generation of active glucocorticoid by NADPH-dependent, 11β-hydroxysteroid dehydrogenase type 1 (11β-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 11β-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 11β-HSD1 oxoreductase activity and add a new dimension to the investigation of 11β-HSD1 as a therapeutic target in patients with the metabolic syndrome.

Original languageEnglish (US)
Pages (from-to)6546-6551
Number of pages6
JournalJournal of Biological Chemistry
Volume281
Issue number10
DOIs
StatePublished - Mar 10 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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