Contribution of local regeneration of glucocorticoids to tissue steroid pools

Shazia Khan; Dawn E. W Livingstone; Agnieszka Zielinska; Craig L Doig; Diego F Cobice; Cristina L Esteves; Janet Tak Yun Man; Natalie Z.M. Homer; Jonathan R Seckl; C.Logan Mackay; Scott P Webster; Gareth G Lavery; Karen E Chapman; Brian R Walker; Ruth Andrew

doi:10.1530/JOE-23-0034

Contribution of local regeneration of glucocorticoids to tissue steroid pools

Shazia Khan, Dawn E. W Livingstone, Agnieszka Zielinska, Craig L Doig, Diego F Cobice, Cristina L Esteves, Janet Tak Yun Man, Natalie Z.M. Homer, Jonathan R Seckl, C.Logan Mackay, Scott P Webster, Gareth G Lavery, Karen E Chapman, Brian R Walker, Ruth Andrew

Research output: Contribution to journal › Article › peer-review

Abstract

11β-Hydroxysteroid dehydrogenase 1 (11βHSD1) is a drug target to attenuate adverse effects of chronic glucocorticoid excess. It catalyses intracellular regeneration of active glucocorticoids in tissues including brain, liver and adipose tissue (coupled to hexose-6-phosphate dehydrogenase, H6PDH). 11βHSD1 activity in individual tissues is thought to contribute significantly to glucocorticoid levels at those sites, but its local contribution versus glucocorticoid delivery via the circulation is unknown. Here, we hypothesised that hepatic 11βHSD1 would contribute significantly to the circulating pool. This was studied in mice with Cre-mediated disruption of Hsd11b1 in liver (Alac-Cre) versus adipose tissue (aP2-Cre) or whole-body disruption of H6pdh. Regeneration of [9,12,12-2 46 H3]-cortisol (d3F) from [9,12,12-2 47 H3]-cortisone (d3E), measuring 11βHSD1 reductase activity was assessed at steady state following infusion of [9,11,12,12-2 48 H4]-cortisol (d4F) in male mice. Concentrations of steroids in plasma and amounts in liver, adipose tissue and brain were measured using mass spectrometry interfaced with matrix assisted laser desorption ionisation or liquid chromatography. Amounts of d3F were higher in liver, compared with brain and adipose tissue. Rates of appearance of d3F were ~6-fold slower in H6pdh-/- 52 mice, showing the importance of whole-body 11βHSD1 reductase activity. Disruption of liver 11βHSD1 reduced amounts of d3F in liver (by ~36%), without changes elsewhere. In contrast disruption of 11βHSD1 in adipose tissue reduced rates of appearance of circulating d3F (by ~67%) and also reduced regeneration of d3F in liver and brain (both by ~30%). Thus, the contribution of hepatic 11βHSD1 to circulating glucocorticoid levels and amounts in other tissues is less than that of adipose tissue.

Original language	English
Journal	Journal of Endocrinology
Early online date	1 Jun 2023
DOIs	https://doi.org/10.1530/JOE-23-0034
Publication status	E-pub ahead of print - 1 Jun 2023

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Tissue-specific control of cortisol versus corticosterone in humans
Walker, B. (Principal Investigator)
UK-based charities
1/02/16 → 30/06/22
Project: Research
Research Excellence Award - Cardiovascular Surgery / Zebrafish Support
Mullin, N. (Principal Investigator), Azzoni, E. (Co-investigator), Fox, K. (Co-investigator), Mullins, J. (Co-investigator), Newby, D. (Co-investigator), Seckl, J. (Co-investigator), Walker, B. (Co-investigator), Webb, D. (Co-investigator) & Wilmut, I. (Co-investigator)
UK-based charities
1/04/08 → 30/09/17
Project: Research

Edinburgh Clinical Research Facility Mass Spectrometry Core in the QMRI
Homer, N. (Manager), Denham, S. (Other) & Simpson, J. (Other)
Centre for Cardiovascular Science
Facility/equipment: Facility
Edinburgh Drug Discovery
Unciti-Broceta, A. (Manager), Webster, S. (Manager) & Carragher, N. (Manager)
Deanery of Molecular, Genetic and Population Health Sciences
Facility/equipment: Facility

Cite this

Khan, S., Livingstone, D. E. W., Zielinska, A., Doig, C. L., Cobice, D. F., Esteves, C. L., Man, J. T. Y., Homer, N. Z. M., Seckl, J. R., Mackay, C. L., Webster, S. P., Lavery, G. G., Chapman, K. E., Walker, B. R., & Andrew, R. (2023). Contribution of local regeneration of glucocorticoids to tissue steroid pools. Journal of Endocrinology . Advance online publication. https://doi.org/10.1530/JOE-23-0034

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title = "Contribution of local regeneration of glucocorticoids to tissue steroid pools",

abstract = "11β-Hydroxysteroid dehydrogenase 1 (11βHSD1) is a drug target to attenuate adverse effects of chronic glucocorticoid excess. It catalyses intracellular regeneration of active glucocorticoids in tissues including brain, liver and adipose tissue (coupled to hexose-6-phosphate dehydrogenase, H6PDH). 11βHSD1 activity in individual tissues is thought to contribute significantly to glucocorticoid levels at those sites, but its local contribution versus glucocorticoid delivery via the circulation is unknown. Here, we hypothesised that hepatic 11βHSD1 would contribute significantly to the circulating pool. This was studied in mice with Cre-mediated disruption of Hsd11b1 in liver (Alac-Cre) versus adipose tissue (aP2-Cre) or whole-body disruption of H6pdh. Regeneration of [9,12,12-2 46 H3]-cortisol (d3F) from [9,12,12-2 47 H3]-cortisone (d3E), measuring 11βHSD1 reductase activity was assessed at steady state following infusion of [9,11,12,12-2 48 H4]-cortisol (d4F) in male mice. Concentrations of steroids in plasma and amounts in liver, adipose tissue and brain were measured using mass spectrometry interfaced with matrix assisted laser desorption ionisation or liquid chromatography. Amounts of d3F were higher in liver, compared with brain and adipose tissue. Rates of appearance of d3F were ~6-fold slower in H6pdh-/- 52 mice, showing the importance of whole-body 11βHSD1 reductase activity. Disruption of liver 11βHSD1 reduced amounts of d3F in liver (by ~36%), without changes elsewhere. In contrast disruption of 11βHSD1 in adipose tissue reduced rates of appearance of circulating d3F (by ~67%) and also reduced regeneration of d3F in liver and brain (both by ~30%). Thus, the contribution of hepatic 11βHSD1 to circulating glucocorticoid levels and amounts in other tissues is less than that of adipose tissue.",

author = "Shazia Khan and Livingstone, {Dawn E. W} and Agnieszka Zielinska and Doig, {Craig L} and Cobice, {Diego F} and Esteves, {Cristina L} and Man, {Janet Tak Yun} and Homer, {Natalie Z.M.} and Seckl, {Jonathan R} and C.Logan Mackay and Webster, {Scott P} and Lavery, {Gareth G} and Chapman, {Karen E} and Walker, {Brian R} and Ruth Andrew",

note = "Funding Information: The work was supported by British Heart Foundation (RG-05-00 8; 2011) and its Centre for Research Excellence (BHF RE/08/001; 2008-date), and Publisher Copyright: {\textcopyright} 2023 the author(s).",

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doi = "10.1530/JOE-23-0034",

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T1 - Contribution of local regeneration of glucocorticoids to tissue steroid pools

AU - Khan, Shazia

AU - Livingstone, Dawn E. W

AU - Zielinska, Agnieszka

AU - Doig, Craig L

AU - Cobice, Diego F

AU - Esteves, Cristina L

AU - Man, Janet Tak Yun

AU - Homer, Natalie Z.M.

AU - Seckl, Jonathan R

AU - Mackay, C.Logan

AU - Webster, Scott P

AU - Lavery, Gareth G

AU - Chapman, Karen E

AU - Walker, Brian R

AU - Andrew, Ruth

N1 - Funding Information: The work was supported by British Heart Foundation (RG-05-00 8; 2011) and its Centre for Research Excellence (BHF RE/08/001; 2008-date), and Publisher Copyright: © 2023 the author(s).

PY - 2023/6/1

Y1 - 2023/6/1

N2 - 11β-Hydroxysteroid dehydrogenase 1 (11βHSD1) is a drug target to attenuate adverse effects of chronic glucocorticoid excess. It catalyses intracellular regeneration of active glucocorticoids in tissues including brain, liver and adipose tissue (coupled to hexose-6-phosphate dehydrogenase, H6PDH). 11βHSD1 activity in individual tissues is thought to contribute significantly to glucocorticoid levels at those sites, but its local contribution versus glucocorticoid delivery via the circulation is unknown. Here, we hypothesised that hepatic 11βHSD1 would contribute significantly to the circulating pool. This was studied in mice with Cre-mediated disruption of Hsd11b1 in liver (Alac-Cre) versus adipose tissue (aP2-Cre) or whole-body disruption of H6pdh. Regeneration of [9,12,12-2 46 H3]-cortisol (d3F) from [9,12,12-2 47 H3]-cortisone (d3E), measuring 11βHSD1 reductase activity was assessed at steady state following infusion of [9,11,12,12-2 48 H4]-cortisol (d4F) in male mice. Concentrations of steroids in plasma and amounts in liver, adipose tissue and brain were measured using mass spectrometry interfaced with matrix assisted laser desorption ionisation or liquid chromatography. Amounts of d3F were higher in liver, compared with brain and adipose tissue. Rates of appearance of d3F were ~6-fold slower in H6pdh-/- 52 mice, showing the importance of whole-body 11βHSD1 reductase activity. Disruption of liver 11βHSD1 reduced amounts of d3F in liver (by ~36%), without changes elsewhere. In contrast disruption of 11βHSD1 in adipose tissue reduced rates of appearance of circulating d3F (by ~67%) and also reduced regeneration of d3F in liver and brain (both by ~30%). Thus, the contribution of hepatic 11βHSD1 to circulating glucocorticoid levels and amounts in other tissues is less than that of adipose tissue.

AB - 11β-Hydroxysteroid dehydrogenase 1 (11βHSD1) is a drug target to attenuate adverse effects of chronic glucocorticoid excess. It catalyses intracellular regeneration of active glucocorticoids in tissues including brain, liver and adipose tissue (coupled to hexose-6-phosphate dehydrogenase, H6PDH). 11βHSD1 activity in individual tissues is thought to contribute significantly to glucocorticoid levels at those sites, but its local contribution versus glucocorticoid delivery via the circulation is unknown. Here, we hypothesised that hepatic 11βHSD1 would contribute significantly to the circulating pool. This was studied in mice with Cre-mediated disruption of Hsd11b1 in liver (Alac-Cre) versus adipose tissue (aP2-Cre) or whole-body disruption of H6pdh. Regeneration of [9,12,12-2 46 H3]-cortisol (d3F) from [9,12,12-2 47 H3]-cortisone (d3E), measuring 11βHSD1 reductase activity was assessed at steady state following infusion of [9,11,12,12-2 48 H4]-cortisol (d4F) in male mice. Concentrations of steroids in plasma and amounts in liver, adipose tissue and brain were measured using mass spectrometry interfaced with matrix assisted laser desorption ionisation or liquid chromatography. Amounts of d3F were higher in liver, compared with brain and adipose tissue. Rates of appearance of d3F were ~6-fold slower in H6pdh-/- 52 mice, showing the importance of whole-body 11βHSD1 reductase activity. Disruption of liver 11βHSD1 reduced amounts of d3F in liver (by ~36%), without changes elsewhere. In contrast disruption of 11βHSD1 in adipose tissue reduced rates of appearance of circulating d3F (by ~67%) and also reduced regeneration of d3F in liver and brain (both by ~30%). Thus, the contribution of hepatic 11βHSD1 to circulating glucocorticoid levels and amounts in other tissues is less than that of adipose tissue.

U2 - 10.1530/JOE-23-0034

DO - 10.1530/JOE-23-0034

M3 - Article

SN - 0022-0795

JO - Journal of Endocrinology

JF - Journal of Endocrinology

ER -

Contribution of local regeneration of glucocorticoids to tissue steroid pools

Abstract

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Projects

Tissue-specific control of cortisol versus corticosterone in humans

Research Excellence Award - Cardiovascular Surgery / Zebrafish Support

Equipment

Edinburgh Clinical Research Facility Mass Spectrometry Core in the QMRI

Edinburgh Drug Discovery

Cite this