FFAR4/GPR120 ACTIVATION COUNTERACTS FIBROGENIC PATHWAYS IN A CHOLESTATIC LIVER INJURY MODEL

Free fatty acids (FFAs) are non-esterified fatty acids that act as natural ligands for a group of G protein-coupled receptors known as FFARs (free fatty acid receptors or G-protein coupled receptors, GPRs), including FFAR4 (GPR120)1. Unsaturated FFAs may play a direct role in improving liver diseases, including cholestatic conditions, which are characterized by reduced bile flow caused bydysfunction of hepatocytes and cholangiocytes2. This can progress to extensive fibrosis and functional impairment of the organ, treatable only by transplantation. Based on this evidence, the project aims to evaluate the effect of a selective GPR120 agonist (GprA) on liver fibrosis in a murine model of cholestasis induced surgically through bile duct ligation (BDL), and to compare its effects with those of obeticholic acid (OCA), a drug used in the treatment of primary biliary cirrhosis3. GprA was well tolerated by the treated animals, which showed significantly higher survival than the vehicle- treated BDL group. Further evaluations demonstrated that GprA did not show positive effects in modulating the main inflammatory interleukins 1α, -1β, -4, -5, -10, and -6. However, the agonist reduced the expression of key pro-fibrotic markers, including collagens I and III, connective tissue growth factor (CTGF), and α- SMA. Finally, GprA interacts with enzymes involved in extracellular matrix remodeling, leading to a noticeable reduction in the fibrogenic process. Based on the obtained results, the test of the efficacy of GprA in other experimental models of fibrosis could represent an important objective in the effort to identify effective molecules for the treatment of various unresolved liver diseases.