Fatty acid mimetic PBI-4547 restores metabolic homeostasis via GPR84 in mice with non-alcoholic fatty liver disease.

Autor: Simard JC; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Thibodeau JF; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada. j.thibodeau@liminalbiosciences.com.; Department of Cellular and Molecular Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada. j.thibodeau@liminalbiosciences.com., Leduc M; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Tremblay M; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Laverdure A; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Sarra-Bournet F; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Gagnon W; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Ouboudinar J; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Gervais L; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Felton A; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Letourneau S; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Geerts L; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Cloutier MP; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Hince K; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Corpuz R; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Blais A; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Quintela VM; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Duceppe JS; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Abbott SD; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Blais A; Department of Cellular and Molecular Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada., Zacharie B; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Laurin P; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Laplante SR; Institut National de La Recherche Scientifique, Institut Armand-Frappier, 531 Boul. Des Prairies, Laval, QC, H7V 5B7, Canada., Kennedy CRJ; Department of Cellular and Molecular Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada., Hébert RL; Department of Cellular and Molecular Medicine, Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada., Leblond FA; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Grouix B; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada., Gagnon L; Liminal R&D Biosciences Inc., 500 Boulevard Cartier Ouest (Suite 150), Laval, QC, H7V 5B7, Canada.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2020 Jul 29; Vol. 10 (1), pp. 12778. Date of Electronic Publication: 2020 Jul 29.
DOI: 10.1038/s41598-020-69675-8
Abstrakt: Non-alcoholic Fatty Liver Disease (NAFLD) is the most common form of liver disease and is associated with metabolic dysregulation. Although G protein-coupled receptor 84 (GPR84) has been associated with inflammation, its role in metabolic regulation remains elusive. The aim of our study was to evaluate the potential of PBI-4547 for the treatment of NAFLD and to validate the role of its main target receptor, GPR84. We report that PBI-4547 is a fatty acid mimetic, acting concomitantly as a GPR84 antagonist and GPR40/GPR120 agonist. In a mouse model of diet-induced obesity, PBI-4547 treatment improved metabolic dysregulation, reduced hepatic steatosis, ballooning and NAFLD score. PBI-4547 stimulated fatty acid oxidation and induced gene expression of mitochondrial uncoupling proteins in the liver. Liver metabolomics revealed that PBI-4547 improved metabolic dysregulation induced by a high-fat diet regimen. In Gpr84 -/- mice, PBI-4547 treatment failed to improve various key NAFLD-associated parameters, as was observed in wildtype littermates. Taken together, these results highlight a detrimental role for the GPR84 receptor in the context of meta-inflammation and suggest that GPR84 antagonism via PBI-4547 may reflect a novel treatment approach for NAFLD and its related complications.
Databáze: MEDLINE
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