Contribution of local regeneration of glucocorticoids to tissue steroid pools

Author:

Khan S1ORCID,Livingstone D E W12ORCID,Zielinska A3,Doig C L4ORCID,Cobice D F1,Esteves C L1,Man J T Y1,Homer N Z M5,Seckl J R1,MacKay C L6,Webster S P1,Lavery G G4,Chapman K E1,Walker B R17,Andrew R15ORCID

Affiliation:

1. Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK

2. Centre for Discovery Brain Science, University of Edinburgh, Hugh Robson Building, Edinburgh, UK

3. College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

4. Department of Biosciences, School of Science & Technology, Nottingham Trent University, Nottingham, UK

5. Mass Spectrometry Core Laboratory, Edinburgh Clinical Research Facility, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK

6. SIRCAMS, School of Chemistry, University of Edinburgh, Joseph Black Building, King's Buildings, Edinburgh, UK

7. Clinical & Translational Research Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK

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 vs 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) vs adipose tissue (aP2-Cre) or whole-body disruption of H6pdh. Regeneration of [9,12,12-2H3]-cortisol (d3F) from [9,12,12-2H3]-cortisone (d3E), measuring 11βHSD1 reductase activity was assessed at steady state following infusion of [9,11,12,12-2H4]-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−/− mice, showing the importance for whole-body 11βHSD1 reductase activity. Disruption of liver 11βHSD1 reduced the 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 regenerated 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.

Publisher

Bioscientifica

Subject

Endocrinology,Endocrinology, Diabetes and Metabolism

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