Beneficial effects of UDCA and norUDCA in a rodent model of steatosis are linked to modulation of GPBAR1/FXR signaling |
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| Institution: | 1. University of Perugia, Department of Medicine and Surgery, Perugia, Italy;2. University of Naples Federico II, Department of Pharmacy, Naples, Italy;3. Department of Pharmacy, University of Salerno, Italy;4. Azienda Ospedaliera di Perugia, Perugia, Italy;1. Univ. Grenoble Alpes, Inserm, LBFA, U1055, UFR STAPS, Grenoble, France;2. LBEPS, Univ Evry, IRBA, Université Paris Saclay, Evry, France;3. Aix Marseille Univ, CNRS, CRMBM, Marseille, France;4. Univ. Grenoble Alpes, Inserm, HP2, U1042, Grenoble, France;5. Univ. Grenoble Alpes, Inserm, LBFA, U1055, CHU Grenoble Alpes, Grenoble, France;6. Univ. Grenoble Alpes, Inserm, LBFA, U1055, Grenoble, France;1. Institut de Recherches Cliniques de Montréal (IRCM), affiliated to the Université de Montréal, Montreal, QC, Canada;2. Equipe SP@RTE, UMR 6290 CNRS, Université de Rennes 1, Rennes, France;3. Nantes Université, CHU Nantes, CNRS, INSERM, l''Institut du thorax, F-44000 Nantes, France;4. Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada;5. S.L. present address: Centre de recherche de l''hôpital Maisonneuve Rosemont, Montreal, QC, Canada;1. Division of Molecular Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, USA;2. Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA;1. New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China;2. Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China;3. Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China;4. Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China |
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| Abstract: | Non-alcoholic steatosis (NAFLD) and steatohepatitis (NASH) are two highly prevalent human disorders for which therapy remains suboptimal. Bile acids play an essential role in regulating liver metabolism, and several bile acids-based therapy are currently investigated for their potential therapeutic efficacy in NAFLD/NASH. Bile acids exert their functions, at least in part, by modulating two main receptors the Farnesoid-x-receptor (FXR) and the G protein-coupled receptor, GPBAR1. In the present study we have compared the pharmacological effects of two bile acids, the ursodeoxycholic acid (UDCA) and its derivative norUDCA, in a model of NAFLD/NASH induced by feeding mice with a Western diet for 12 weeks. The results of these studies demonstrated that both UDCA and norUDCA protected against development of steatosis and fibrosis, but did not reduce the hepatocytes ballooning nor the development of a pro-atherogenic lipid profile. Both agents reduced liver lipogenesis and ameliorated insulin sensitivity and adipocytes signaling as shown by increased expression of adiponectin. Mechanistically, UDCA acts as weak GPBAR1 agonist, while norUDCA exerted no effect on both GPBAR1 and FXR. In vivo administration of UDCA resets bile acid synthesis and promotes a shift toward bile acids species that are GPBAR1 agonists, UDCA, TUDCA and hyodeoxycholic acid, and increases GLP1 expression in the ileum. In contrast norUDCA is poorly metabolized exerting a minimal impact on GPBAR1 signaling. Together, these data, highlight the potential role of UDCA and norUDCA in treating of NAFLD, though these beneficial effects are supported by different mechanisms. |
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