Peptides from Harpadon nehereus protect against hyperglycemia-induced HepG2 via oxidative stress and glycolipid metabolism regulation.

[Display omitted] • Three oligopeptides with antioxidant and anti-hyperglycemic activities, KA-8, LR-7, and PG-7, were isolated from fish bone hydrolysate for the first time. • They protect against hyperglycemia-induced HepG2 via oxidative stress and glycolipid metabolism regulation. • LR-7 inhibits Keap1-Nrf2 protein–protein interaction, thereby promoting Nrf2 expression and nuclear transfer. • KA-8 exert its protective role through AKT/GSK-3β signaling pathway activation. Three oligopeptides of KLHDEEVA (KA-8), LALFVPR (LR-7), and PSRILYG (PG-7) were selected from the hydrolysate of Harpadon nehereus. They significantly improved cell morphology and decreased aspartate aminotransferase (AST), alanine transaminase (ALT), and reactive oxygen species (ROS) levels in high glucose-induced HepG2 cells. LR-7 showed good performance in regulating both antioxidant and glucose metabolism in high glucose-induced HepG2 cells, evidenced by improved expression levels of glucose-6-phosphatase (G6Pase), phosphoenolpyruvate carboxykinase 1 (PEPCK1), heme-oxygenase (HO-1), NAD(P)H: quinone oxidoreductase 1 (NQO1), and nuclear factor E2-related factor 2 (Nrf2). PG-7 had better performance in reducing triglyceride (TG) and total cholesterol (TC) levels and enhancing superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity levels. KA-8 showed stronger effects on improving low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), phosphorylation protein kinase B (p-AKT), and phosphorylation glycogen synthase kinase-3 (p-GSK-3β) levels. The results showed that all three peptides could protect against high glucose-induced HepG2 damage through different molecular mechanisms. The protective effects of LR-7 may be attributed mainly to its excellent glycolipid metabolism regulation and oxidative stress attenuation via Nrf2 pathway activation. KA-8 may exert its protective role through AKT/GSK-3β signaling pathway activation. [ABSTRACT FROM AUTHOR]