Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a major health concern with no approved pharmacological therapies. 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...
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MDPI AG
2022-06-01
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| author | Justine Gillard Corinne Picalausa Christoph Ullmer Luciano Adorini Bart Staels Anne Tailleux Isabelle A. Leclercq |
| author_facet | Justine Gillard Corinne Picalausa Christoph Ullmer Luciano Adorini Bart Staels Anne Tailleux Isabelle A. Leclercq |
| author_sort | Justine Gillard |
| collection | DOAJ |
| description | Metabolic dysfunction-associated fatty liver disease (MAFLD) is a major health concern with no approved pharmacological therapies. 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 <i>foz/foz</i> 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. |
| first_indexed | 2024-03-09T03:58:59Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6643 |
| language | English |
| last_indexed | 2024-03-09T03:58:59Z |
| publishDate | 2022-06-01 |
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| series | Nutrients |
| spelling | doaj.art-e894aea60f524f7586ce70cd39ceb4c92023-12-03T14:16:42ZengMDPI AGNutrients2072-66432022-06-011413270710.3390/nu14132707Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose DysmetabolismJustine Gillard0Corinne Picalausa1Christoph Ullmer2Luciano Adorini3Bart Staels4Anne Tailleux5Isabelle A. Leclercq6Laboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, 1200 Brussels, BelgiumLaboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, 1200 Brussels, BelgiumPharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, SwitzerlandIntercept Pharmaceuticals, New York, NY 10001, USAInserm, CHU Lille, Institut Pasteur de Lille, University Lille, U1011-EGID, F-59000 Lille, FranceInserm, CHU Lille, Institut Pasteur de Lille, University Lille, U1011-EGID, F-59000 Lille, FranceLaboratory of Hepato-Gastroenterology, Institute of Experimental and Clinical Research, Université Catholique de Louvain, 1200 Brussels, BelgiumMetabolic dysfunction-associated fatty liver disease (MAFLD) is a major health concern with no approved pharmacological therapies. 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 <i>foz/foz</i> 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.https://www.mdpi.com/2072-6643/14/13/2707MAFLDNASHmetabolic syndromeTGR5INT-777RO5527239 |
| spellingShingle | Justine Gillard Corinne Picalausa Christoph Ullmer Luciano Adorini Bart Staels Anne Tailleux Isabelle A. Leclercq Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism Nutrients MAFLD NASH metabolic syndrome TGR5 INT-777 RO5527239 |
| title | Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism |
| title_full | Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism |
| title_fullStr | Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism |
| title_full_unstemmed | Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism |
| title_short | Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism |
| title_sort | enterohepatic takeda g protein coupled receptor 5 agonism in metabolic dysfunction associated fatty liver disease and related glucose dysmetabolism |
| topic | MAFLD NASH metabolic syndrome TGR5 INT-777 RO5527239 |
| url | https://www.mdpi.com/2072-6643/14/13/2707 |
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