Bile acids increase steroidogenesis in cholemic mice and induce cortisol secretion in adrenocortical H295R cells via S1PR2, ERK and SF-1.
Animals
Bile Acids and Salts
/ metabolism
Cell Line
Chenodeoxycholic Acid
/ pharmacology
Cholestasis
/ metabolism
Extracellular Signal-Regulated MAP Kinases
/ metabolism
Glucose
/ metabolism
Humans
Hydrocortisone
/ biosynthesis
Lipid Metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Signal Transduction
Sphingosine-1-Phosphate Receptors
/ metabolism
Steroidogenic Factor 1
/ metabolism
adrenal steroidogenesis
extracellular signal-regulated kinase
sphingosine 1-phosphate receptor 2
steroidogenic factor 1
Journal
Liver international : official journal of the International Association for the Study of the Liver
ISSN: 1478-3231
Titre abrégé: Liver Int
Pays: United States
ID NLM: 101160857
Informations de publication
Date de publication:
11 2019
11 2019
Historique:
received:
18
10
2018
revised:
10
01
2019
accepted:
13
01
2019
pubmed:
22
1
2019
medline:
21
10
2020
entrez:
22
1
2019
Statut:
ppublish
Résumé
Bile acids are now accepted as central signalling molecules for the regulation of glucose, amino acid and lipid metabolism. Adrenal gland cortex cells express the bile acid receptors farnesoid X receptor (FXR), the G protein-coupled bile acid receptor (TGR5) and the sphingosine-1-phosphate receptor 2 (S1PR2). We aimed to determine the effects of cholestasis and more specifically of bile acids on cortisol production. FXR and TGR5 knockout mice and controls were subjected to common bile duct ligation (CBDL) or chenodeoxycholic acid (CDCA) feeding to model cholestasis. Human adrenocortical H295R cells were challenged with bile acids for mechanistic studies. We found that CBDL and CDCA feeding increased the levels of corticosterone, the rodent equivalent to human cortisol and mRNA and protein levels of steroidogenesis-related enzymes in adrenals independent of FXR and TGR5. Taurine-conjugated CDCA (TCDCA) significantly stimulated cortisol secretion, phosphorylation of extracellular signal-regulated kinase (ERK) and expression of steroidogenesis-related genes in human adrenocortical H295R cells. FXR and TGR5 agonists failed to induce cortisol secretion in H295R cells. S1PR2 inhibition significantly abolished TCDCA-induced cortisol secretion, lowered phosphorylation of ERK and abrogated enhanced transcription of steroidogenesis-related genes in H295R cells. Likewise, siRNA S1PR2 treatment reduced the phosphorylation of ERK and cortisol secretion. Steroidogenic factor-1 (SF-1) transactivation activity was increased upon TCDCA treatment suggesting that bile acid signalling is linked to SF-1. Treatment with SF-1 inverse agonist AC45594 also reduced TCDCA-induced steroidogenesis. Our findings indicate that supraphysiological bile acid levels as observed in cholestasis stimulate steroidogenesis via an S1PR2-ERK-SF-1 signalling pathway.
Sections du résumé
BACKGROUND AND AIMS
Bile acids are now accepted as central signalling molecules for the regulation of glucose, amino acid and lipid metabolism. Adrenal gland cortex cells express the bile acid receptors farnesoid X receptor (FXR), the G protein-coupled bile acid receptor (TGR5) and the sphingosine-1-phosphate receptor 2 (S1PR2). We aimed to determine the effects of cholestasis and more specifically of bile acids on cortisol production.
METHODS
FXR and TGR5 knockout mice and controls were subjected to common bile duct ligation (CBDL) or chenodeoxycholic acid (CDCA) feeding to model cholestasis. Human adrenocortical H295R cells were challenged with bile acids for mechanistic studies.
RESULTS
We found that CBDL and CDCA feeding increased the levels of corticosterone, the rodent equivalent to human cortisol and mRNA and protein levels of steroidogenesis-related enzymes in adrenals independent of FXR and TGR5. Taurine-conjugated CDCA (TCDCA) significantly stimulated cortisol secretion, phosphorylation of extracellular signal-regulated kinase (ERK) and expression of steroidogenesis-related genes in human adrenocortical H295R cells. FXR and TGR5 agonists failed to induce cortisol secretion in H295R cells. S1PR2 inhibition significantly abolished TCDCA-induced cortisol secretion, lowered phosphorylation of ERK and abrogated enhanced transcription of steroidogenesis-related genes in H295R cells. Likewise, siRNA S1PR2 treatment reduced the phosphorylation of ERK and cortisol secretion. Steroidogenic factor-1 (SF-1) transactivation activity was increased upon TCDCA treatment suggesting that bile acid signalling is linked to SF-1. Treatment with SF-1 inverse agonist AC45594 also reduced TCDCA-induced steroidogenesis.
CONCLUSIONS
Our findings indicate that supraphysiological bile acid levels as observed in cholestasis stimulate steroidogenesis via an S1PR2-ERK-SF-1 signalling pathway.
Identifiants
pubmed: 30664326
doi: 10.1111/liv.14052
pmc: PMC6899711
doi:
Substances chimiques
Bile Acids and Salts
0
NR5A1 protein, human
0
S1PR2 protein, human
0
Sphingosine-1-Phosphate Receptors
0
Steroidogenic Factor 1
0
Chenodeoxycholic Acid
0GEI24LG0J
Extracellular Signal-Regulated MAP Kinases
EC 2.7.11.24
Glucose
IY9XDZ35W2
Hydrocortisone
WI4X0X7BPJ
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2112-2123Subventions
Organisme : Austrian Science Fund FWF
ID : W 1226
Pays : Austria
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2019 The Authors. Liver International published by John Wiley & Sons Ltd.
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