Antisteatotic and antifibrotic activity of a new synthetic GPR120 receptor agonist in mice overfed with a “Western-style diet”

Several factors such as genetic variants, obesity, and unhealthy lifestyle with unbalanced diets are correlated to the pathogenesis of nonalcoholic fatty liver disease (NAFLD). This is a complex disorder ranging from simple steatosis to inflammation (nonalcoholic fatty liver, NAFL), worsening into fibrosis (nonalcoholic steatohepatitis, NASH). The driving injury is the alteration of lipids homeostasis, leading to an abnormal accumulation of triglycerides and other lipids in the liver parenchyma. Currently, no resolutive pharmacological treatment for NAFLD is available, and the only therapeutic approach is represented by a healthy diet and physical exercise, although many reports suggest the potential druggability of specific receptors for fatty acids to improve liver fitness in many metabolic contexts. In this study, we targeted the G-protein-coupled receptor 120/free fatty acid receptor 4 (GPR120/FFAR4), with a new and specific synthetic agonist, GprA. We monitored the progression of liver damage in mice fed for different periods (26 weeks, NAFL stage; and 30 weeks, NASH stage), with a “Western-style” diet (WSD) and treated daily by oral gavage with 3 doses (30-60-90 mg/Kg) of GprA. The analyses highlighted that GprA is able to reduce signs of steatosis at the two time-point of WSD-fed mice, both at the histological and molecular levels, when used at 90mg/Kg. Furthermore, in NASH-like treated mice, GprA is also effective in the reduction of collagen maturation and deposition, fibrosis development, and connective tissue growth factor (CTGF) expression. Altogether, our data confirm the central role of FFAR4 in the context of NAFL/NASH onset and progression and reveal that GprA could represent an interesting candidate for the development of a new therapeutic approach in NAFL treatment.