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.
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U2 - 10.1074/jbc.M512635200
DO - 10.1074/jbc.M512635200
M3 - Article
C2 - 16356929
AN - SCOPUS:33646007919
SN - 0021-9258
VL - 281
SP - 6546
EP - 6551
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 10
ER -