title: Hexose-6-phosphate dehydrogenase knock-out mice lack 11 beta-hydroxysteroid dehydrogenase type 1-mediated glucocorticoid generation.
abstract: The local generation of active glucocorticoid by NADPH-dependent, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-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 11beta-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 11beta-HSD1 oxoreductase activity and add a new dimension to the investigation of 11beta-HSD1 as a therapeutic target in patients with the metabolic syndrome.
authors.affiliation: Department of Internal Medicine and Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Gareth G
authors.initials: GG
authors.lastname: Lavery
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Walker
authors.forename: Nicole
authors.initials: N
authors.lastname: Draper
authors.forename: Pancharatnam
authors.initials: P
authors.lastname: Jeyasuria
authors.forename: Josep
authors.initials: J
authors.lastname: Marcos
authors.forename: Cedric H L
authors.initials: CH
authors.lastname: Shackleton
authors.forename: Keith L
authors.initials: KL
authors.lastname: Parker
authors.forename: Perrin C
authors.initials: PC
authors.lastname: White
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000502:physiology; D000311:Adrenal Glands / Q000502:physiology; D000818:Animals; D002237:Carbohydrate Dehydrogenases / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D005938:Glucocorticoids / Q000096:biosynthesis*; D007700:Kinetics; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000201:enzymology; D017384:Sequence Deletion
chemical_list: D005938:Glucocorticoids; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1