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Molecules developed to activate the bile acid-receptor TGR5 regulate pathways involved in MALFD pathogenesis, but the therapeutic value of TGR5 activation on the active form of MAFLD, non-alcoholic steatohepatitis (NASH), still needs to be evaluated. As TGR5 agonism is low in MAFLD, we used strategies to promote the production of endogenous TGR5 ligands or administered pharmacological TGR5 agonists, INT-777 and RO5527239, to study the effect of TGR5 activation on liver and metabolic diseases in high-fat diet-fed foz\/foz mice. Although described in the literature, treatment with fexaramine, an intestine-restricted FXR agonist, did not raise the concentrations of TGR5 ligands nor modulate TGR5 signaling and, accordingly, did not improve dysmetabolic status. INT-777 and RO5527239 directly activated TGR5. INT-777 only increased the TGR5 activation capacity of the portal blood; RO5527239 also amplified the TGR5 activation capacity of systemic blood. Both molecules improved glucose tolerance. In spite of the TGR5 activation capacity, INT-777, but not RO5527239, reduced liver disease severity. In conclusion, TGR5 activation in enterohepatic, rather than in peripheral, tissues has beneficial effects on glucose tolerance and MAFLD.<\/jats:p>","DOI":"10.3390\/nu14132707","type":"journal-article","created":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T22:43:28Z","timestamp":1656542608000},"page":"2707","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism"],"prefix":"10.3390","volume":"14","author":[{"given":"Justine","family":"Gillard","sequence":"first","affiliation":[{"name":"Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, Universit\u00e9 Catholique de Louvain, 1200 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Picalausa","sequence":"additional","affiliation":[{"name":"Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, Universit\u00e9 Catholique de Louvain, 1200 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Ullmer","sequence":"additional","affiliation":[{"name":"Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8109-339X","authenticated-orcid":false,"given":"Luciano","family":"Adorini","sequence":"additional","affiliation":[{"name":"Intercept Pharmaceuticals, New York, NY 10001, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3784-1503","authenticated-orcid":false,"given":"Bart","family":"Staels","sequence":"additional","affiliation":[{"name":"Inserm, CHU Lille, Institut Pasteur de Lille, University Lille, U1011-EGID, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Tailleux","sequence":"additional","affiliation":[{"name":"Inserm, CHU Lille, Institut Pasteur de Lille, University Lille, U1011-EGID, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle A.","family":"Leclercq","sequence":"additional","affiliation":[{"name":"Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, Universit\u00e9 Catholique de Louvain, 1200 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and Validation of a Histological Scoring System for Nonalcoholic Fatty Liver Disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global Epidemiology of Nonalcoholic Fatty Liver Disease\u2014Meta-Analytic Assessment of Prevalence, Incidence, and Outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.jhep.2020.03.039","article-title":"A New Definition for Metabolic Dysfunction-Associated Fatty Liver Disease: An International Expert Consensus Statement","volume":"73","author":"Eslam","year":"2020","journal-title":"J. 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