title: Liver-selective transgene rescue of hypothalamic-pituitary-adrenal axis dysfunction in 11beta-hydroxysteroid dehydrogenase type 1-deficient mice.
abstract: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) acts as a reductase in vivo, regenerating active glucocorticoids within cells from circulating inert 11-keto forms, thus amplifying local glucocorticoid action. 11beta-HSD1 is predominantly expressed in liver and also adipose tissue and brain. Mice deficient in 11beta-HSD1 (11beta-HSD1(-/-)) exhibit adrenal hyperplasia, raised basal corticosterone levels, and increased hypothalamic-pituitary-adrenal (HPA) axis responses to stress. Whereas reduced peripheral glucocorticoid regeneration may explain adrenal hypertrophy and exaggerated stress responses, elevated basal glucocorticoid levels support a role for 11beta-HSD1 within the brain in amplifying glucocorticoid feedback. To test this hypothesis, apolipoprotein E-HSD1 mice overexpressing 11beta-HSD1 in liver were intercrossed with 11beta-HSD1(-/-) mice to determine whether complementation of hepatic 11beta-HSD1 can restore adrenal and HPA defects. Transgene-mediated delivery of 11beta-HSD1 activity to the liver rescued adrenal hyperplasia and reversed exaggerated HPA stress responses in 11beta-HSD1(-/-) mice. Unexpectedly, elevated nadir plasma corticosterone levels were also restored to control levels. Consistent with this, CYP11B1 mRNA expression in the adrenal cortex of 11beta-HSD1(-/-) mice was increased by 50% but returned to control levels in 11beta-HSD1(-/-) mice bearing the apolipoprotein E-HSD1 transgene. 11beta-HSD1(-/-) mice have lower plasma glucose levels, but the fall in plasma corticosterone with sucrose supplementation was similar in 11beta-HSD1(-/-) and control mice, suggesting glucose deficiency is not the main mechanism whereby basal corticosterone levels are elevated in the null mice. Thus, regeneration of glucocorticoids by 11beta-HSD1 in the liver normalizes all aspects of HPA axis dysregulation in 11beta-HSD1(-/-) mice, without restoration of enzyme activity in key feedback areas of the forebrain. Therefore, hepatic glucocorticoid metabolism influences basal as well as stress-associated functions of the HPA axis.
authors.affiliation: Centre for Cardiovascular Science, Endocrinology Unit, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Paterson
authors.forename: Megan C
authors.initials: MC
authors.lastname: Holmes
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kenyon
authors.forename: Roderick
authors.initials: R
authors.lastname: Carter
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics* / Q000378:metabolism; D000311:Adrenal Glands / Q000378:metabolism; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics / Q000628:therapy; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D002940:Circadian Rhythm; D003345:Corticosterone / Q000097:blood; D015316:Genetic Therapy; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000503:physiopathology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009928:Organ Specificity; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000503:physiopathology*; D019076:Transgenes
chemical_list: D001057:Apolipoproteins E; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone