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

Sci Rep. 2020 Jul 29;10(1):12778. doi: 10.1038/s41598-020-69675-8.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / pharmacology*
  • Animals
  • Binding, Competitive
  • Biosensing Techniques
  • Cholesterol / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Drug Discovery
  • Fatty Acids / pharmacology*
  • Female
  • Glucose / metabolism
  • Glucose Tolerance Test
  • HEK293 Cells
  • Homeostasis
  • Humans
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Male
  • Metabolomics
  • Mice
  • Mitochondria / metabolism
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Obesity / metabolism
  • Oxygen / metabolism
  • Plasmids / metabolism
  • Protein Binding
  • Receptors, G-Protein-Coupled / metabolism*


  • Acetates
  • Fatty Acids
  • Gpr84 protein, mouse
  • Ligands
  • PBI-4547
  • Receptors, G-Protein-Coupled
  • Cholesterol
  • Glucose
  • Oxygen