TGR5 controls bile acid composition and gallbladder function to protect the liver from bile acid overload

Autor: Bidault-Jourdainne, Valeska, Merlen, Grégory, Glénisson, Mathilde, Doignon, Isabelle, Garcin, Isabelle, Péan, Noémie, Boisgard, Raphaël, Ursic-Bedoya, José, Serino, Matteo, Ullmer, Christoph, Humbert, Lydie, Abdelrafee, Ahmed, Golse, Nicolas, Vibert, Eric, Duclos-Vallée, Jean-Charles, Rainteau, Dominique, Tordjmann, Thierry
Přispěvatelé: HAL-SU, Gestionnaire, Récepteur TGR5 des acides biliaires et réparation du foie - - BaTiLiRe2015 - ANR-15-CE14-0007 - AAPG2015 - VALID, Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Roche Pharma Research and Early Development [Basel] (pRED), F. Hoffmann-La Roche [Basel], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Hépato-Biliaire [Hôpital Paul Brousse] (CHB), Hôpital Paul Brousse-Assistance Publique - Hôpitaux de Paris, ANR-15-CE14-0007,BaTiLiRe,Récepteur TGR5 des acides biliaires et réparation du foie(2015), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: JHEP Reports Innovation in Hepatology
JHEP Reports Innovation in Hepatology, 2021, 3 (2), pp.100214. ⟨10.1016/j.jhepr.2020.100214⟩
JHEP Reports Innovation in Hepatology, Elsevier, 2021, 3 (2), pp.100214. ⟨10.1016/j.jhepr.2020.100214⟩
JHEP Reports
JHEP Reports, Vol 3, Iss 2, Pp 100214-(2021)
ISSN: 2589-5559
DOI: 10.1016/j.jhepr.2020.100214⟩
Popis: Background & Aims 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 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 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 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 Through multiple in vivo experimental approaches in mice, together with a patient study, this work brings some new light on the relationships between biliary homeostasis, gallbladder function, and liver protection. We showed that hepatic bile acid composition is crucial for optimal liver repair, not only in mice, but also in human patients undergoing major hepatectomy.
Graphical abstract
Highlights • Reducing BA hydrophobicity improves outcomes after major hepatectomy in mice. • The BA receptor TGR5 controls BA pool composition, which is crucial for liver repair. • TGR5 targets the gallbladder to induce a hepatoprotective effect. • In patients, a more hydrophobic BA pool is associated with liver injury after hepatectomy.
Databáze: OpenAIRE
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