Bile acids contribute to the development of non-alcoholic steatohepatitis in mice
| العنوان: | Bile acids contribute to the development of non-alcoholic steatohepatitis in mice |
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| المؤلفون: | Justine Gillard, Laure-Alix Clerbaux, Bart Staels, Anne Tailleux, Isabelle Leclercq, Laure B. Bindels, Maxime Nachit, Christine Sempoux |
| المساهمون: | UCL - SSS/LDRI - Louvain Drug Research Institute, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (SLuc) Service de gastro-entérologie |
| المصدر: | JHEP reports, vol. 4, no. 1, pp. 100387 JHEP Reports, Vol 4, Iss 1, Pp 100387-(2022) JHEP reports, Vol. 4, no.1, p. 100387 [1-13] (2022) JHEP Reports |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | HFD, high-fat diet, CYP7A1, CYP8B1, sterol 12α-hydroxylase, WDF, western and high-fructose diet, FABP6, OGTT, oral glucose tolerance test, FGF15, RC799-869, ASBT, apical sodium-dependent BA transporter, chemistry.chemical_compound, OST, organic solute transporter, βMCA, β-muricholic acid, SHP, small heterodimer protein, WDF, CYP27A1, SHP, TNFα, Immunology and Allergy, LCA, lithocholic acid, DCA, FABP6, fatty acid binding protein 6, FGFR4, fibroblast growth factor receptor 4, CA, cholic acid, NAS, NAFLD activity score, CA, CYP7B1, CYP7B1, oxysterol 7α-hydroxylase, Bile acid, WT, αMCA, ND, normal diet, TGR5, Takeda G-protein coupled receptor 5, Chemistry, LCA, Deoxycholic acid, TLCA, TGR5, Gastroenterology, NASH, GLP-1, glucagon-like peptide-1, Diseases of the digestive system. Gastroenterology, G protein-coupled bile acid receptor, TNFα, tumor necrosis factor α, FXR, BA, bile acid, LPS, lipopolysaccharide, Research Article, CYP2A12, bile acid 7α-hydroxylase, ωMCA, NAFLD, non-alcoholic fatty liver disease, medicine.medical_specialty, ωMCA, ω-muricholic acid, LPS, normal diet, Normal diet, βMCA, medicine.drug_class, NASH, non-alcoholic steatohepatitis, education, tumor necrosis factor α, BA, digestive system, metabolic syndrome, CDCA, chenodeoxycholic acid, CYP2A12, CYP27A1, sterol 27-hydroxylase, Internal medicine, NAFLD, Internal Medicine, medicine, OGTT, CYP7A1, cholesterol 7α-hydroxylase, DCA, deoxycholic acid, FGF15, fibroblast growth factor 15, FXR, Farnesoid X receptor, TLCA, tauro-lithocholic acid, WT, wild-type, αMCA, α-muricholic acid, wild-type, CYP8B1, Hepatology, OST, medicine.disease, Endocrinology, NAS, FGFR4, CDCA, HFD, ND, Steatohepatitis, GLP-1, ASBT |
| الوصف: | 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. Graphical abstract Highlights • The enterohepatic bile acid profile is profoundly altered in mice with NASH. • Bile acid signaling through FXR and TGR5 is dampened in mice with NASH. • Modulation of bile acid composition prevents obesity, insulin resistance and NASH. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a4f803f3cd8976e73d533d8b1885ead5Test https://serval.unil.ch/notice/serval:BIB_8BED7E41CA16Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a4f803f3cd8976e73d533d8b1885ead5 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |