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 journalArticle

158 Citations (Scopus)

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

Fingerprint

11-beta-Hydroxysteroid Dehydrogenases
Corticosterone
Knockout Mice
Glucocorticoids
NADP
Adiposity
Gene Silencing
Endoplasmic Reticulum
Oxidoreductases
Genes
Glucose
galactose-6-phosphate dehydrogenase
Liver
Enzymes
11-dehydrocorticosterone

ASJC Scopus subject areas

  • Biochemistry

Cite this

Lavery, G. G., Walker, E. A., Draper, N., Jeyasuria, P., Marcos, J., Shackleton, C. H. L., ... Stewart, P. M. (2006). Hexose-6-phosphate dehydrogenase knock-out mice lack 11β- hydroxysteroid dehydrogenase type 1-mediated glucocorticoid generation. Journal of Biological Chemistry, 281(10), 6546-6551. https://doi.org/10.1074/jbc.M512635200

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

In: Journal of Biological Chemistry, Vol. 281, No. 10, 10.03.2006, p. 6546-6551.

Research output: Contribution to journalArticle

Lavery, GG, Walker, EA, Draper, N, Jeyasuria, P, Marcos, J, Shackleton, CHL, Parker, KL, White, PC & Stewart, PM 2006, 'Hexose-6-phosphate dehydrogenase knock-out mice lack 11β- hydroxysteroid dehydrogenase type 1-mediated glucocorticoid generation', Journal of Biological Chemistry, vol. 281, no. 10, pp. 6546-6551. https://doi.org/10.1074/jbc.M512635200
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. / Hexose-6-phosphate dehydrogenase knock-out mice lack 11β- hydroxysteroid dehydrogenase type 1-mediated glucocorticoid generation. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 10. pp. 6546-6551.
@article{c844c3a20af243268a63a96ab77f4c5c,
title = "Hexose-6-phosphate dehydrogenase knock-out mice lack 11β- hydroxysteroid dehydrogenase type 1-mediated glucocorticoid generation",
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.",
author = "Lavery, {Gareth G.} and Walker, {Elizabeth A.} and Nicole Draper and Pancharatnam Jeyasuria and Josep Marcos and Shackleton, {Cedric H L} and Parker, {Keith L.} and White, {Perrin C.} and Stewart, {Paul M.}",
year = "2006",
month = "3",
day = "10",
doi = "10.1074/jbc.M512635200",
language = "English (US)",
volume = "281",
pages = "6546--6551",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "10",

}

TY - JOUR

T1 - Hexose-6-phosphate dehydrogenase knock-out mice lack 11β- hydroxysteroid dehydrogenase type 1-mediated glucocorticoid generation

AU - Lavery, Gareth G.

AU - Walker, Elizabeth A.

AU - Draper, Nicole

AU - Jeyasuria, Pancharatnam

AU - Marcos, Josep

AU - Shackleton, Cedric H L

AU - Parker, Keith L.

AU - White, Perrin C.

AU - Stewart, Paul M.

PY - 2006/3/10

Y1 - 2006/3/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=33646007919&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646007919&partnerID=8YFLogxK

U2 - 10.1074/jbc.M512635200

DO - 10.1074/jbc.M512635200

M3 - Article

C2 - 16356929

AN - SCOPUS:33646007919

VL - 281

SP - 6546

EP - 6551

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 10

ER -