Mulberrin from Morus alba modulates lipid metabolism associated with PPARα/CPT-1-mediated fatty acid oxidation and CYP7A1-related cholesterol metabolism

The present research studied the regulation effect of mulberrin (MUL) from Morus alba on lipid metabolism and its mechanism of action. The results indicated that MUL effectively inhibited the formation of lipid droplets, total triglycerides (TG), and total cholesterol (TC) in fat-accumulated HepG2 cells. RT-qPCR and western blotting analysis demonstrated that MUL regulated lipid metabolism through the peroxisome proliferator-activated receptor α (PPARα)/carnitine palmitoyltransferase-1 (CPT-1) associated fatty acid oxidation and cholesterol 7α-hydroxylase (CYP7A1)-related cholesterol metabolism. Caco-2/HepG2 Transwell co-culture model was further established to investigate the metabolic pathways of MUL from intestinal absorption to target cells. Non-targeted metabolomics analysis indicated that MUL treatment was associated with alterations in key differential metabolites involved in sphingolipid metabolism, α-linolenic acid metabolism, fatty acid metabolism, cholesterol metabolism, arachidonic acid metabolism, cytochrome P450 metabolism pathway related to lipid as evidenced by KEGG analysis. The integration of signaling analysis with metabolomic profiling suggested that MUL might exert multi-target regulatory effects on lipid homeostasis at both cellular and metabolic network levels. These findings provide a systems-level perspective on the lipid-regulatory potential of MUL.