TGR5 controls bile acid composition and gallbladder function to protect the liver from bile acid overload.
ALP, alkaline phosphatase
ALT, alanine aminotransferase
BA, bile acid
BDL, bile duct ligation
Bile acids
CA, cholic acid
CC, cholecystectomy
CT, cholestyramine
CYP, cytochrome P450
EH, extended hepatectomy
GB, gallbladder
GM, gut microbiota
GPBAR1
GPBAR1, G protein-coupled bile acid receptor 1
Gallbladder
HI, hydrophobicity index
Hepatoprotection
KO, knockout
ND, normal diet
OA, oleanolic acid
PH, partial hepatectomy
TBA, total BA
TGR5
TGR5, Takeda G protein coupled receptor
UDCA, ursodeoxycholic acid
WT, wild-type
Journal
JHEP reports : innovation in hepatology
ISSN: 2589-5559
Titre abrégé: JHEP Rep
Pays: Netherlands
ID NLM: 101761237
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
received:
20
05
2020
revised:
29
10
2020
accepted:
30
10
2020
entrez:
19
2
2021
pubmed:
20
2
2021
medline:
20
2
2021
Statut:
epublish
Résumé
As the composition of the bile acid (BA) pool has a major impact on liver pathophysiology, we studied its regulation by the BA receptor Takeda G protein coupled receptor (TGR5), which promotes hepatoprotection against BA overload. Wild-type, total and hepatocyte-specific TGR5-knockout, and TGR5-overexpressing mice were used in: partial (66%) and 89% extended hepatectomies (EHs) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (CA)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied the impact of TGR5 on: BA composition, liver injury, regeneration and survival. We also performed analyses on the gut microbiota (GM) and gallbladder (GB). Liver BA composition was analysed in patients undergoing major hepatectomy. The TGR5-KO hyperhydrophobic BA composition was not directly related to altered BA synthesis, nor to TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and co-housing experiments, respectively. The TGR5-dependent control of GB dilatation was crucial for BA composition, as determined by experiments including RO treatment and/or cholecystectomy. The poor TGR5-KO post-EH survival rate, related to exacerbated peribiliary necrosis and BA overload, was improved by shifting BAs toward a less toxic composition (CT treatment). After either BDL or a CA-enriched diet with or without cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic liver BA composition was correlated with an unfavourable outcome after hepatectomy. BA composition is crucial for hepatoprotection in mice and humans. We indicate TGR5 as a key regulator of BA profile and thereby as a potential hepatoprotective target under BA overload conditions. Through multiple
Sections du résumé
BACKGROUND & AIMS
OBJECTIVE
As the composition of the bile acid (BA) pool has a major impact on liver pathophysiology, we studied its regulation by the BA receptor Takeda G protein coupled receptor (TGR5), which promotes hepatoprotection against BA overload.
METHODS
METHODS
Wild-type, total and hepatocyte-specific TGR5-knockout, and TGR5-overexpressing mice were used in: partial (66%) and 89% extended hepatectomies (EHs) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (CA)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied the impact of TGR5 on: BA composition, liver injury, regeneration and survival. We also performed analyses on the gut microbiota (GM) and gallbladder (GB). Liver BA composition was analysed in patients undergoing major hepatectomy.
RESULTS
RESULTS
The TGR5-KO hyperhydrophobic BA composition was not directly related to altered BA synthesis, nor to TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and co-housing experiments, respectively. The TGR5-dependent control of GB dilatation was crucial for BA composition, as determined by experiments including RO treatment and/or cholecystectomy. The poor TGR5-KO post-EH survival rate, related to exacerbated peribiliary necrosis and BA overload, was improved by shifting BAs toward a less toxic composition (CT treatment). After either BDL or a CA-enriched diet with or without cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic liver BA composition was correlated with an unfavourable outcome after hepatectomy.
CONCLUSIONS
CONCLUSIONS
BA composition is crucial for hepatoprotection in mice and humans. We indicate TGR5 as a key regulator of BA profile and thereby as a potential hepatoprotective target under BA overload conditions.
LAY SUMMARY
BACKGROUND
Through multiple
Identifiants
pubmed: 33604531
doi: 10.1016/j.jhepr.2020.100214
pii: S2589-5559(20)30148-8
pmc: PMC7872982
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100214Informations de copyright
© 2020 The Authors.
Déclaration de conflit d'intérêts
The authors declare no conflicts of interest that pertain to this work.
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