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Liver-Selective Transgene Rescue of Hypothalamic-Pituitary-Adrenal Axis Dysfunction in 11ß-Hydroxysteroid Dehydrogenase Type 1-Deficient Mice

Molecular Physiology Group (J.M.P., J.J.M.) and Endocrinology Unit (M.C.H., C.J.K., R.C., J.R.S.), Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Professor Jonathan Seckl, Centre for Cardiovascular Science, Endocrinology Unit, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom. E-mail: j.seckl{at}ed.ac.uk.

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) acts as a reductase in vivo, regenerating active glucocorticoids within cells from circulating inert 11-keto forms, thus amplifying local glucocorticoid action. 11ß-HSD1 is predominantly expressed in liver and also adipose tissue and brain. Mice deficient in 11ß-HSD1 (11ß-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 11ß-HSD1 within the brain in amplifying glucocorticoid feedback. To test this hypothesis, apolipoprotein E-HSD1 mice overexpressing 11ß-HSD1 in liver were intercrossed with 11ß-HSD1^–/– mice to determine whether complementation of hepatic 11ß-HSD1 can restore adrenal and HPA defects. Transgene-mediated delivery of 11ß-HSD1 activity to the liver rescued adrenal hyperplasia and reversed exaggerated HPA stress responses in 11ß-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 11ß-HSD1^–/– mice was increased by 50% but returned to control levels in 11ß-HSD1^–/– mice bearing the apolipoprotein E-HSD1 transgene. 11ß-HSD1^–/– mice have lower plasma glucose levels, but the fall in plasma corticosterone with sucrose supplementation was similar in 11ß-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 11ß-HSD1 in the liver normalizes all aspects of HPA axis dysregulation in 11ß-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.

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