Peptides from Harpadon nehereus Bone Ameliorate Sodium Palmitate-Induced HepG2 Lipotoxicity by Regulating Oxidative Stress and Lipid Metabolism

Antioxidant peptides are a well-known functional food exhibiting multiple biological activities in health and disease. This study investigated the effects of three peptides, LR-7 (LALFVPR), KA-8 (KLHDEEVA), and PG-7 (PSRILYG), from <i>Harpadon nehereus</i> bone on sodium palmitate (PANa)-induced HepG2. The findings indicated that all three peptides significantly reduced the oxidative damage and fat accumulation in the HepG2 cells while also normalizing the abnormal blood lipid levels caused by PANa. Furthermore, treatment with LR-7 resulted in a more than 100% increase in catalase (CAT), glutathione peroxidase (GSH-Px), and nuclear factor erythroid 2-related factor 2 (Nrf2) levels within the HepG2 cells (<i>p</i> < 0.001). Western blot analysis showed that LR-7 treatment significantly lowered the expression of fatty acid synthase (FASN) by 59.6% (<i>p</i> < 0.001) while enhancing carnitine palmitoyl transferase 1 (CPT1) by 134.7% (<i>p</i> < 0.001) and adipose triglyceride lipase (ATGL) by 148.1% (<i>p</i> < 0.001). Additionally, these peptides effectively inhibited the pancreatic lipase activity. Notably, LR-7 demonstrated superior effectiveness across all of the evaluated parameters, likely due to its greater hydrophobicity. In summary, LR-7, KA-8, and PG-7 are effective at mitigating oxidative stress as well as regulating lipid metabolism, thus protecting HepG2 cells from PANa-induced injury and lipid buildup. This research indicates that these collagen-derived peptides, especially LR-7, show promise as natural agents for managing hyperlipidemia.