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

2020; Nature Portfolio; Volume: 10; Issue: 1 Linguagem: Inglês

10.1038/s41598-020-69675-8

2045-2322

Jean-Christophe Simard, Jean-François Thibodeau, Martin Leduc, Mikaël Tremblay, Alexandre Laverdure, François Sarra‐Bournet, William Gagnon, Jugurtha Ouboudinar, Liette Gervais, Alexandra Felton, Sylvie Létourneau, Lilianne Geerts, Marie-Pier Cloutier, Kathy Hince, Ramon Corpuz, Alexandra Blais, Vanessa Marques Quintela, Jean‐Simon Duceppe, Shaun Abbott, Amélie Blais, Boulos Zacharie, Pierre Laurin, Steven R. LaPlante, C. Kennedy, Richard Hébert, François A. Leblond, Brigitte Grouix, Lyne Gagnon,

Diet, Metabolism, and Disease

Abstract 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.