Glucocorticoids regulate AKR1D1 activity in human liver in vitro and in vivo
File(s)
Author(s)
Type
Journal Article
Abstract
Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates endogenous glucocorticoids and catalyses an important step in bile acid synthesis. Endogenous and synthetic glucocorticoids are potent regulators of metabolic phenotype and play a crucial role in hepatic glucose metabolism. However, the potential of synthetic glucocorticoids to be metabolised by AKR1D1 as well as to regulate its expression and activity has not been investigated. The impact of glucocorticoids on AKR1D1 activity was assessed in human liver HepG2 and Huh7 cells; AKR1D1 expression was assessed by qPCR and Western blotting. Genetic manipulation of AKR1D1 expression was conducted in HepG2 and Huh7 cells and metabolic assessments were made using qPCR. Urinary steroid metabolite profiling in healthy volunteers was performed pre- and post-dexamethasone treatment, using gas chromatography-mass spectrometry. AKR1D1 metabolised endogenous cortisol, but cleared prednisolone and dexamethasone less efficiently. In vitro and in vivo, dexamethasone decreased AKR1D1 expression and activity, further limiting glucocorticoid clearance and augmenting action. Dexamethasone enhanced gluconeogenic and glycogen synthesis gene expression in liver cell models and these changes were mirrored by genetic knockdown of AKR1D1 expression. The effects of AKR1D1 knockdown were mediated through multiple nuclear hormone receptors, including the glucocorticoid, pregnane X and farnesoid X receptors. Glucocorticoids down-regulate AKR1D1 expression and activity and thereby reduce glucocorticoid clearance. In addition, AKR1D1 down-regulation alters the activation of multiple nuclear hormone receptors to drive changes in gluconeogenic and glycogen synthesis gene expression profiles, which may exacerbate the adverse impact of exogenous glucocorticoids.
Date Issued
2020-05-01
Date Acceptance
2020-02-27
Citation
Journal of Endocrinology, 2020, 245 (2), pp.207-218
ISSN
0022-0795
Publisher
BioScientifica
Start Page
207
End Page
218
Journal / Book Title
Journal of Endocrinology
Volume
245
Issue
2
Copyright Statement
© 2020 The authors 2020. This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/)
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/32106090
PII: JOE-19-0473.R1
Subjects
5β-reductase
NAFLD
dexamethasone
gluconeogenesis
glycogen
liver
Adult
Cells, Cultured
Gene Expression Regulation, Enzymologic
Glucocorticoids
Gluconeogenesis
Healthy Volunteers
Hepatocytes
Humans
Liver
Male
Oxidoreductases
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2020-05-01