P3-1 Alleviates NAFLD by Regulating the Liver-Gut Axis and PPARα/RXRα Pathway in Mice

Plant-derived peptides show hepatoprotective biological functions. An octapeptide (Gly-Phe-Cys-Asp-Arg-Met-Pro-Leu), termed P3-1, was isolated from macadamia nuts for the first time. This study evaluated the ameliorative effect of P3-1 on nonalcoholic fatty liver disease (NAFLD) and clarified the molecular basis of this action. The results showed that P3-1 attenuated hepatic pathological damage, improved lipid metabolism and liver function indices, and enhanced antioxidant capacity in NAFLD mice. In addition, P3-1 enhanced intestinal barrier function, thereby improving hepatic metabolic function and inflammatory status by restoring gut microbiota balance. P3-1 alleviated lipid peroxidation by activating key NAFLD-related signaling pathways involving PPARα/RXRα. P3-1 regulated the expression of lipid metabolism-related genes, including APOA1, FASN, SCD-1, and FABP1, and suppressed NF-κB expression, thereby effectively attenuating inflammatory responses. These results indicate that P3-1 improves lipid metabolism and inflammatory status by modulating the liver-gut axis and shows potential as a functional health-oriented food ingredient.