The GPR40 full agonist SCO-267 improves liver parameters in a mouse model of nonalcoholic fatty liver disease without affecting glucose or body weight

Full agonism of G-protein-coupled receptor 40 (GPR40)/free fatty acid 1 (FFA1) receptor improves glycemic control in diabetic rodents. However, the effects of GPR40 full agonism on liver parameters are largely unknown. In the present study, we examined the effects of a GPR40 full agonist, SCO-267, on liver parameters in a non-diabetic mouse model with early-stage nonalcoholic fatty liver disease (NAFLD). SCO-267 was orally administered to mice, which were fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), a mouse model for NAFLD. An oral dose of SCO-267 increased levels of circulating glucagon and glucagon-like peptide-1 in CDAHFD-fed mice. In a chronic dose experiment, effects of SCO-267 were compared with those of a dipeptidyl peptidase-4 inhibitor (alogliptin) and a sodium glucose co-transporter 2 inhibitor (dapagliflozin). SCO-267 decreased liver triglyceride content, weight, and collagen content, and plasma alanine aminotransferase (ALT) levels without affecting food intake or glucose levels in CDAHFD-fed mice. Furthermore, SCO-267 decreased levels of liver thiobarbituric acid reactive substances (TBARS), markers of oxidative stress. Alogliptin and dapagliflozin had no effect on liver weight or levels of triglyceride, collagen, plasma ALT, and liver TBARS. SCO-267 elevated mRNA levels of molecules with roles in mitochondrial function and beta-oxidation, while inhibiting those with roles in lipogenesis, inflammation, reactive oxygen species generation, and fibrosis in the liver, all of which were less evident with alogliptin and dapagliflozin. This is the first study to show that the GPR40 full agonist, SCO-267, improves liver parameters without affecting glucose or body weight in a mouse model of NAFLD. Significance Statement Full agonism of GPR40/FFA1 receptor signaling stimulates islet and gut hormone secretions. The present study is the first to show the treatment effects of GPR40 full agonism on liver parameters in a mouse model for nonalcoholic fatty liver disease.