Therapeutic effects of blue mussel-derived peptides (PIISVYWK and FSVVPSPK) on non-alcoholic fatty liver disease by modulating lipid metabolism and inflammation in high-fat diet-induced mice

Non-alcoholic fatty liver disease (NAFLD) is a progressive condition, advancing from simple hepatic lipid accumulation to inflammation, fibrosis, and increased risk of mortality. This study explores the therapeutic efficacy of bioactive peptides PIISVYWK (P1) and FSVVPSPK (P2) in ameliorating NAFLD in both oleic acid-treated HepG2 cells and high-fat diet (HFD)-induced mice. Our findings demonstrated that P1 and P2 significantly reduced hepatic fat deposition, enhanced lipolysis by promoting the release of free glycerol and free fatty acids, and suppressed key de novo lipogenesis-related proteins, including peroxisome proliferator-activated receptor γ (PPARγ), CCAAT-enhancer-binding protein α (C/EBPα), sterol regulatory element-binding protein 1 (SREBP-1), and fatty acid synthase (FAS). Furthermore, both peptides stimulated fatty acid oxidation via phosphorylation of AMP-activated protein kinase (AMPK) and hormone-sensitive lipase (HSL). Notably, reductions in body and liver weight, along with improved cholesterol profiles and liver function markers (alanine transaminase and aspartate aminotransferase), were observed in HFD mice. Additionally, P1 and P2 significantly attenuated the production of pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in both in vitro and in vivo models. Collectively, these results highlight the potent therapeutic potential of P1 and P2 in mitigating NAFLD progression, offering a promising intervention for this increasingly prevalent metabolic disorder.