Abstract
Full agonism of G-protein-coupled receptor 40 (GPR40)/free fatty acid 1 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 nondiabetic 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 cotransporter 2 inhibitor (dapagliflozin). SCO-267 decreased liver triglyceride content, weight, 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 β-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/free fatty acid 1 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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver diseases ranging from noninflammatory isolated steatosis, characterized by triglyceride accumulation in hepatocytes, to nonalcoholic steatohepatitis (NASH), a more advanced form of the disease, which is characterized by steatosis, inflammation, and hepatocyte cell ballooning associated with liver fibrosis (Arab et al, 2018)
Effects of SCO-267, a G-protein–coupled receptor 40 (GPR40) full agonist, on liver-related parameters were evaluated in CDAHFD-fed mice, a nondiabetic animal model for NAFLD
To the best of our knowledge, this report is the first to demonstrate that a GPR40 full agonist improved abnormal liver-related conditions in a preclinical NAFLD disease model
Summary
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver diseases ranging from noninflammatory isolated steatosis, characterized by triglyceride accumulation in hepatocytes, to nonalcoholic steatohepatitis (NASH), a more advanced form of the disease, which is characterized by steatosis, inflammation, and hepatocyte cell ballooning associated with liver fibrosis (Arab et al, 2018). NAFLD is a major cause of other liver disease worldwide and will likely emerge as the leading cause of end-stage liver disease in the future. Weight loss and lifestyle changes are considered to be effective ways to overcome NAFLD (Wattacheril et al, 2018). Because of the lack of approved drugs, there is an urgent need for development of effective pharmacological treatments for patients with NAFLD (Wattacheril et al, 2018). The pathogenesis of NAFLD is complex and still unclear.
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