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

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 endopla...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2006-03, Vol.281 (10), p.6546-6551
Main Authors: Lavery, Gareth G., Walker, Elizabeth A., Draper, Nicole, Jeyasuria, Pancharatnam, Marcos, Josep, Shackleton, Cedric H.L., Parker, Keith L., White, Perrin C., Stewart, Paul M.
Format: Article
Language:English
Subjects:
11-beta-Hydroxysteroid Dehydrogenase Type 1 - physiology
Adrenal Glands - physiology
Animals
Carbohydrate Dehydrogenases - deficiency
Carbohydrate Dehydrogenases - genetics
Female
Glucocorticoids - biosynthesis
Kinetics
Male
Metabolic Syndrome - drug therapy
Metabolic Syndrome - enzymology
Mice
Mice, Inbred C57BL
Mice, Knockout
Microsomes, Liver - enzymology
Sequence Deletion
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M512635200