The GPR40 Full Agonist SCO-267 Improves Liver Parameters in a Mouse Model of Nonalcoholic Fatty Liver Disease without Affecting Glucose or Body Weight

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 b-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.

SCO-267, a GPR40 Full Agonist, Stimulates Islet and Gut Hormone Secretion and Improves Glycemic Control in Humans

“…Moreover, glucagon plays a pivotal role in lipid metabolism (29). In a preclinical setting, SCO-267, which stimulates the secretion of GLP-1 and glucagon, has been shown to improve liver function parameters in mice with nonalcoholic fatty liver disease (15). These findings suggest the potential for SCO-267-mediated glucagon secretion to play a role in the treatment of hepatic steatosis and nonalcoholic fatty liver disease in clinical settings.…”

“…This unique feature of GPR40 full agonists results in more effective glycemic control than that achieved by the partial agonists, as demonstrated in preclinical models (11). In addition to the treatment potential for diabetes, full agonists of GPR40 may also exhibit therapeutic efficacy in the treatment of obesity and nonalcoholic fatty liver disease (15,16). The clinical profiles of full agonists of GPR40 have not yet been evaluated.…”

Omega-3 fatty acids coordinate glucose and lipid metabolism in diabetic patients

“…For instance, G-protein coupled receptor 120 (GPR120) is a functional receptor for alpha-linolenic acid [ 30 ] expressed on endocrine L-cells lining the gut which has been shown to directly mediate PUFA-induced increases in glucagon like peptide-1 (GLP-1) [ 31 ]. Other receptors activated by free fatty acids include GPR40, mostly engaged by long chain fatty acids, GPR84 engaged by medium chain fatty acids, and GPR41 and GPR43, engaged by short chain fatty acids [ 32 – 34 ]. An action on pancreatic islets (direct or mediated by GLP-1 [ 35 – 37 ]), or on hepatic and adipose tissue, represent other, not mutually exclusive possibilities.…”

SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection

“…Treatment with both remogliflozin and ipragliflozin also reduced oxidative stress levels, as evaluated by decreased thiobarbituric acid reactive substances (TBARS) levels [ 100 , 134 ]. Instead, administration of dapagliflozin at 1 mg/kg/twice/day for four weeks had no significant effect either on hepatic TBARS and TG levels or on plasma ALT levels [ 135 ]. In addition, reduction of oxidative stress by empagliflozin treatment resulted in amelioration of hepatic inflammation [ 30 , 107 , 116 ] and steatosis, as judged by down-regulation of inflammatory markers [ 30 , 107 , 115 ].…”