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.
Highlights
Non-alcoholic Fatty Liver Disease (NAFLD) is the most common form of liver disease and is associated with metabolic dysregulation
Studies evaluating the role of G protein-coupled receptor 84 (GPR84) in glucose and fatty acid (FA) metabolism have been quite limited[20]
PBI-4547, a fatty acid mimetic, was used as a tool to study the role of GPR84 in glucose/FA metabolism and in NAFLD development
Summary
Non-alcoholic Fatty Liver Disease (NAFLD) is the most common form of liver disease and is associated with metabolic dysregulation. NAFLD represents the pathological hepatic manifestation of metabolic dysregulation including fatty acid (FA) metabolism, not caused by excessive alcohol consumption, pro-steatogenic drugs or hereditary disorders and is defined by the presence of steatosis in the liver, due to triglyceride accumulation in hepatocytes (> 5% of total fat content)[1]. FAO is mainly regulated by CD36, one of the scavenger receptors responsible for the uptake of FFA, while FA transport inside the mitochondria is regulated by carnitine palmitoyltransferase 1 (CPT1) Both cellular uptake and mitochondrial translocation are considered the rate limiting steps in FA metabolism. It’s been shown that in human fat cells derived from pre-adipocytes, GPR84 expression levels are induced by pro-inflammatory signals, including TNF-α, IL-1β10 and IL-33, a member of the IL-1β superfamily[11]. Adipose tissue GPR84 expression is higher in morbidly obese compared to non-obese individuals (NCBI GEO Profiles, accession GDS5056), while adipose tissue from diabetics have higher GPR84 levels in CD14 + monocytes than non-diabetics (accession GDS5167)
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