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

Simard, Jean-Christophe; Thibodeau, Jean-François; Leduc, Martin; Tremblay, Mikael; Laverdure, Alexandre; Sarra-Bournet, Francois; Gagnon, William; Ouboudinar, Jugurtha; Gervais, Liette; Felton, Alexandra; Letourneau, Sylvie; Geerts, Lilianne; Cloutier, Marie-Pier; Hince, Kathy; Corpuz, Ramon; Blais, Alexandra; Marques Quintela, Vanessa; Duceppe, Jean-Simon; Abbott, Shaun D; Blais, Amélie; Zacharie, Boulos; Laurin, Pierre; Laplante, Steven ORCID: https://orcid.org/0000-0003-2835-5789; Kennedy, Christopher R J; Hébert, Richard L; Leblond, François A.; Grouix, Brigitte et Gagnon, Lyne (2020). Fatty acid mimetic PBI-4547 restores metabolic homeostasis via GPR84 in mice with non-alcoholic fatty liver disease Scientific Reports , vol. 10 , nº 12778. pp. 1-16. DOI: 10.1038/s41598-020-69675-8.

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Résumé

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.

Type de document:	Article
Mots-clés libres:	-
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	22 juill. 2021 21:36
Dernière modification:	15 févr. 2022 18:48
URI:	https://espace.inrs.ca/id/eprint/11687

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