AKR1D1 regulates glucocorticoid availability and glucocorticoid receptor activation in human hepatoma cells.
5β-reductase
AKR1D1
GR
Glucocorticoids
Steroid hormones
Journal
The Journal of steroid biochemistry and molecular biology
ISSN: 1879-1220
Titre abrégé: J Steroid Biochem Mol Biol
Pays: England
ID NLM: 9015483
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
06
11
2018
revised:
05
02
2019
accepted:
11
02
2019
pubmed:
16
2
2019
medline:
22
11
2019
entrez:
16
2
2019
Statut:
ppublish
Résumé
Steroid hormones, including glucocorticoids and androgens, have potent actions to regulate many cellular processes within the liver. The steroid A-ring reductase, 5β-reductase (AKR1D1), is predominantly expressed in the liver, where it inactivates steroid hormones and, in addition, plays a crucial role in bile acid synthesis. However, the precise functional role of AKR1D1 to regulate steroid hormone action in vitro has not been demonstrated. We have therefore hypothesised that genetic manipulation of AKR1D1 has the potential to regulate glucocorticoid availability and action in human hepatocytes. In both liver (HepG2) and non-liver cell (HEK293) lines, AKR1D1 over-expression increased glucocorticoid clearance with a concomitant decrease in the activation of the glucocorticoid receptor and the down-stream expression of glucocorticoid target genes. Conversely, knockdown of AKR1D1 using siRNA decreased glucocorticoid clearance and reduced the generation of 5β-reduced metabolites. In addition, the two 5α-reductase inhibitors finasteride and dutasteride failed to effectively inhibit AKR1D1 activity in either cell-free or hepatocellular systems. Through manipulation of AKR1D1 expression and activity, we have demonstrated its potent ability to regulate glucocorticoid availability and receptor activation within human hepatoma cells. These data suggest that AKR1D1 may have an important role in regulating endogenous (and potentially exogenous) glucocorticoid action that may be of particular relevance to physiological and pathophysiological processes affecting the liver.
Identifiants
pubmed: 30769091
pii: S0960-0760(18)30682-4
doi: 10.1016/j.jsbmb.2019.02.002
pmc: PMC7375835
mid: NIHMS1609499
pii:
doi:
Substances chimiques
Glucocorticoids
0
Receptors, Glucocorticoid
0
Oxidoreductases
EC 1.-
3-oxo-5 beta-steroid delta 4-dehydrogenase
EC 1.3.99.6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
218-227Subventions
Organisme : British Heart Foundation
ID : FS/15/56/31645
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P011462/1
Pays : United Kingdom
Organisme : NIEHS NIH HHS
ID : P30 ES013508
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.
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