Bile acids contribute to the development of non-alcoholic steatohepatitis in mice

Background & Aims: Through FXR and TGR5 signaling, bile acids (BAs) modulate lipid and glucose metabolism, inflammation and fibrosis. Hence, BAs returning to the liver after enteric secretion, modification and reabsorption may contribute to the pathogenesis of non-alcoholic steatohepatitis (...

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Autores principales:	Justine Gillard, Laure-Alix Clerbaux, Maxime Nachit, Christine Sempoux, Bart Staels, Laure B. Bindels, Anne Tailleux, Isabelle A. Leclercq
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	NAFLD NASH TGR5 FXR metabolic syndrome Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/d288e103d667458db40d774aae2af880
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spelling	oai:doaj.org-article:d288e103d667458db40d774aae2af8802021-11-18T04:51:17ZBile acids contribute to the development of non-alcoholic steatohepatitis in mice2589-555910.1016/j.jhepr.2021.100387https://doaj.org/article/d288e103d667458db40d774aae2af8802022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589555921001634https://doaj.org/toc/2589-5559Background & Aims: Through FXR and TGR5 signaling, bile acids (BAs) modulate lipid and glucose metabolism, inflammation and fibrosis. Hence, BAs returning to the liver after enteric secretion, modification and reabsorption may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH). Herein, we characterized the enterohepatic profile and signaling of BAs in preclinical models of NASH, and explored the consequences of experimental manipulation of BA composition. Methods: We used high-fat diet (HFD)-fed foz/foz and high-fructose western diet-fed C57BL/6J mice, and compared them to their respective controls. Mice received a diet supplemented with deoxycholic acid (DCA) to modulate BA composition. Results: Compared to controls, mice with NASH had lower concentrations of BAs in their portal blood and bile, while systemic BA concentrations were not significantly altered. Notably, the concentrations of secondary BAs, and especially of DCA, and the ratio of secondary to primary BAs were strikingly lower in bile and portal blood of mice with NASH. Hence, portal blood was poor in FXR and TGR5 ligands, and conferred poor anti-inflammatory protection in mice with NASH. Enhanced primary BAs synthesis and conversion of secondary to primary BAs in NASH livers contributed to the depletion in secondary BAs. Dietary DCA supplementation in HFD-fed foz/foz mice restored the BA concentrations in portal blood, increased TGR5 and FXR signaling, improved the dysmetabolic status, protected from steatosis and hepatocellular ballooning, and reduced macrophage infiltration. Conclusions: BA composition in the enterohepatic cycle, but not in systemic circulation, is profoundly altered in preclinical models of NASH, with specific depletion in secondary BAs. Dietary correction of the BA profile protected from NASH, supporting a role for enterohepatic BAs in the pathogenesis of NASH. Lay summary: This study clearly demonstrates that the alterations of enterohepatic bile acids significantly contribute to the development of non-alcoholic steatohepatitis in relevant preclinical models. Indeed, experimental modulation of bile acid composition restored perturbed FXR and TGR5 signaling and prevented non-alcoholic steatohepatitis and associated metabolic disorders.Justine GillardLaure-Alix ClerbauxMaxime NachitChristine SempouxBart StaelsLaure B. BindelsAnne TailleuxIsabelle A. LeclercqElsevierarticleNAFLDNASHTGR5FXRmetabolic syndromeDiseases of the digestive system. GastroenterologyRC799-869ENJHEP Reports, Vol 4, Iss 1, Pp 100387- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	NAFLD NASH TGR5 FXR metabolic syndrome Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	NAFLD NASH TGR5 FXR metabolic syndrome Diseases of the digestive system. Gastroenterology RC799-869 Justine Gillard Laure-Alix Clerbaux Maxime Nachit Christine Sempoux Bart Staels Laure B. Bindels Anne Tailleux Isabelle A. Leclercq Bile acids contribute to the development of non-alcoholic steatohepatitis in mice
description	Background & Aims: Through FXR and TGR5 signaling, bile acids (BAs) modulate lipid and glucose metabolism, inflammation and fibrosis. Hence, BAs returning to the liver after enteric secretion, modification and reabsorption may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH). Herein, we characterized the enterohepatic profile and signaling of BAs in preclinical models of NASH, and explored the consequences of experimental manipulation of BA composition. Methods: We used high-fat diet (HFD)-fed foz/foz and high-fructose western diet-fed C57BL/6J mice, and compared them to their respective controls. Mice received a diet supplemented with deoxycholic acid (DCA) to modulate BA composition. Results: Compared to controls, mice with NASH had lower concentrations of BAs in their portal blood and bile, while systemic BA concentrations were not significantly altered. Notably, the concentrations of secondary BAs, and especially of DCA, and the ratio of secondary to primary BAs were strikingly lower in bile and portal blood of mice with NASH. Hence, portal blood was poor in FXR and TGR5 ligands, and conferred poor anti-inflammatory protection in mice with NASH. Enhanced primary BAs synthesis and conversion of secondary to primary BAs in NASH livers contributed to the depletion in secondary BAs. Dietary DCA supplementation in HFD-fed foz/foz mice restored the BA concentrations in portal blood, increased TGR5 and FXR signaling, improved the dysmetabolic status, protected from steatosis and hepatocellular ballooning, and reduced macrophage infiltration. Conclusions: BA composition in the enterohepatic cycle, but not in systemic circulation, is profoundly altered in preclinical models of NASH, with specific depletion in secondary BAs. Dietary correction of the BA profile protected from NASH, supporting a role for enterohepatic BAs in the pathogenesis of NASH. Lay summary: This study clearly demonstrates that the alterations of enterohepatic bile acids significantly contribute to the development of non-alcoholic steatohepatitis in relevant preclinical models. Indeed, experimental modulation of bile acid composition restored perturbed FXR and TGR5 signaling and prevented non-alcoholic steatohepatitis and associated metabolic disorders.
format	article
author	Justine Gillard Laure-Alix Clerbaux Maxime Nachit Christine Sempoux Bart Staels Laure B. Bindels Anne Tailleux Isabelle A. Leclercq
author_facet	Justine Gillard Laure-Alix Clerbaux Maxime Nachit Christine Sempoux Bart Staels Laure B. Bindels Anne Tailleux Isabelle A. Leclercq
author_sort	Justine Gillard
title	Bile acids contribute to the development of non-alcoholic steatohepatitis in mice
title_short	Bile acids contribute to the development of non-alcoholic steatohepatitis in mice
title_full	Bile acids contribute to the development of non-alcoholic steatohepatitis in mice
title_fullStr	Bile acids contribute to the development of non-alcoholic steatohepatitis in mice
title_full_unstemmed	Bile acids contribute to the development of non-alcoholic steatohepatitis in mice
title_sort	bile acids contribute to the development of non-alcoholic steatohepatitis in mice
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/d288e103d667458db40d774aae2af880
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Bile acids contribute to the development of non-alcoholic steatohepatitis in mice

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